Ligands for metals and improved metal-catalyzed processes based thereon

ABSTRACT

One aspect of the present invention relates to ligands for transition metals. A second aspect of the present invention relates to the use of catalysts comprising these ligands in transition metal-catalyzed carbon-heteroatom and carbon-carbon bond-forming reactions. The subject methods provide improvements in many features of the transition metal-catalyzed reactions, including the range of suitable substrates, reaction conditions, and efficiency.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. Ser. No. 10/420,950,filed Apr. 22, 2003 now U.S. Pat. No. 6,946,560; which is a division ofU.S. Ser. No. 10/004,101, filed Oct. 23, 2001 now U.S. Pat. No.7,026,498; which is a continuation of U.S. Ser. No. 09/231,315, filedJan. 13, 1999, now U.S. Pat. No. 6,307,087; which is acontinuation-in-part of U.S. Ser. No. 09/113,478, filed Jul. 10, 1998,now U.S. Pat. No. 6,395,916.

This application claims the benefit of the filing date of U.S.Provisional Patent Application Ser. No. 60/451,562, filed Mar. 3, 2003;and U.S. Provisional Patent Application Ser. No. 60/431,870, filed Dec.9, 2002.

GOVERNMENT FUNDING

This invention was made with support under Grant Number 9421982-CHE,awarded by the National Science Foundation; the government, therefore,has certain rights in the invention.

BACKGROUND OF THE INVENTION

Transition metal catalyst complexes play important roles in many areasof chemistry, including the preparation of polymers and pharmaceuticals.The properties of these catalyst complexes are recognized to beinfluenced by both the characteristics of the metal and those of theligands associated with the metal atom. For example, structural featuresof the ligands can influence reaction rate, regioselectivity, andstereoselectivity. Bulky ligands can be expected to slow reaction rate;electron-withdrawing ligands, in coupling reactions, can be expected toslow oxidative addition to, and speed reductive elimination from, themetal center; and electron-rich ligands, in coupling reactions,conversely, can be expected to speed oxidative addition to, and slowreductive elimination from, the metal center.

In many cases, the oxidative addition step in the accepted mechanism ofa coupling reaction is deemed to be rate limiting. Therefore,adjustments to the catalytic system as a whole that increase the rate ofthe oxidative addition step should increase overall reaction rate.Additionally, the rate of oxidative addition of a transtion metalcatalyst to the carbon-halogen bond of an aryl halide is known todecrease as the halide is varied from iodide to bromide to chloride, allother factors being equal. Because of this fact, the more stable, lowermolecular weight, and arguably more easy to obtain, members of the groupconsisting of reactive organic halides—the chlorides—are the poorestsubstrates for traditional transition metal catalyzed coupling reactionsand the like.

To date, the best halogen-containing substrates for transtion metalcatalyzed carbon-heteroatom and carbon-carbon bond forming reactionshave been the iodides. Bromides have often been acceptable substrates,but typically required higher temperatures, longer reaction times, andgave lower yields of products.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to novel ligands fortransition metals. A second aspect of the present invention relates tothe use of catalysts comprising these ligands in varioustransition-metal-catalyzed carbon-heteroatom and carbon-carbonbond-forming reactions. The subject methods provide improvements in manyfeatures of transition-metal-catalyzed reactions, including the range ofsuitable substrates, number of catalyst turnovers, reaction conditions,and efficiency.

More specifically, unexpected, pioneering improvements have beenrealized in transition metal-catalyzed: aryl amination reactions; arylamidation reactions; Suzuki couplings to give biaryl products; andα-arylations of ketones. For example, the use of an alcohol, e.g.,tert-butanol, as the solvent in certain methods of the present inventionallows the use of substrates comprising functional groups that wereheretofore precluded because the functional groups were not sufficientlystable to survive the reaction conditions or because they wouldotherwise interfere with the transition-metal-catalyzed methods.Further, the ligands and methods of the present invention enable theefficient use of aryl sulfonates, e.g., aryl tosylates, in theaforementioned reactions.

Additionally, the ligands and methods of the present invention enablefor the first time transformations utilizing aryl bromides or chloridesto proceed efficiently at room temperature. Furthermore, the ligands andmethods of the present invention enable the aforementioned reactions tooccur at synthetically useful rates using extremely small amounts ofcatalyst, e.g., 0.000001 mol % relative to the limiting reagent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts method of preparation and reactions screened for variousligands.

FIG. 2 depicts various embodiments of a carbon-nitrogen bond-formingmethod of the present invention, using various ligands and variousbenzenesulfonates.

FIG. 3 depicts various embodiments of a carbon-nitrogen bond-formingmethod of the present invention, using various ligands and variousbenzenesulfonates.

FIG. 4 depicts various embodiments of a carbon-nitrogen bond-formingmethod of the present invention and a carbon-carbon bond-forming methodof the present invention, using a preferred ligand of the presentinvention and various aryl chlorides.

FIG. 5 depicts various embodiments of a carbon-carbon bond-formingmethod of the present invention, using a preferred ligand of the presentinvention and various aryl chlorides.

FIG. 6 depicts results of a carbon-oxygen bond-forming method of thepresent invention as a function of the ligand of the present inventionused.

FIG. 7 depicts results of a carbon-oxygen bond-forming method of thepresent invention as a function of the ligand of the present inventionused.

FIG. 8 depicts a synthetic protocol for the preparation of a ligand ofthe present invention.

FIG. 9 depicts various embodiments of a carbon-nitrogen bond-formingmethod of the present invention, using a preferred ligand of the presentinvention and 4-butylphenyl chloride, as a function of the base used.

FIG. 10 depicts various embodiments of a carbon-nitrogen bond-formingmethod of the present invention, using a preferred ligand of the presentinvention and 4-butylphenyl chloride, as a function of the base used.

FIG. 11 depicts various embodiments of a carbon-nitrogen bond-formingmethod of the present invention, using a preferred ligand of the presentinvention and 4-butylphenyl chloride, as a function of the amount ofwater in the reaction mixture.

FIG. 12 depicts various embodiments of a carbon-nitrogen bond-formingmethod of the present invention, using a preferred ligand of the presentinvention and various aryl chlorides, as a function of the amount ofwater in the reaction mixture.

FIG. 13 depicts various embodiments of a carbon-nitrogen bond-formingmethod of the present invention, using a preferred ligand of the presentinvention and 4-butylphenyl chloride, as a function of the reactiontime.

FIG. 14 depicts various embodiments of a carbon-carbon bond-formingmethod of the present invention, using as ligand for palladium various(2′,4′,6′-triisopropylbiphenyl)di(alkyl)phosphines, 4-tert-butylphenyltosylate, and phenyl boronic acid. See Example 66.

FIG. 15 depicts various embodiments of a carbon-carbon bond-formingmethod of the present invention, using as ligand for palladium(2′,4′,6′-triisopropylbiphenyl)dicyclohexylphosphine, various aryltosylates, and various aryl boronic acids. See Example 66 and FIG. 14.

FIG. 16 depicts various embodiments of a carbon-carbon bond-formingmethod of the present invention, using as ligand for palladium(2′,4′,6′-triisopropylbiphenyl)dicyclohexylphosphine, various aryltosylates, and various aryl boronic acids. See Example 66 and FIG. 14.

FIG. 17 depicts various embodiments of a carbon-carbon bond-formingmethod of the present invention, using as ligand for palladium(2′,4′,6′-triisopropylbiphenyl)dicyclohexylphosphine, various aryltosylates, and various aryl boronic acids. See Example 66 and FIG. 14.

FIG. 18 depicts various embodiments of a carbon-carbon bond-formingmethod of the present invention, using as ligand for palladium various(2′,4′,6′-triisopropylbiphenyl)di(alkyl)phosphines, various aryltosylates, and various aryl boronic acids. See Example 66 and FIG. 14.

FIG. 19 depicts various embodiments of a carbon-carbon bond-formingmethod of the present invention, using as ligand for palladium(2′,4′,6′-triisopropylbiphenyl)dicyclohexylphosphine, various aryltosylates, and various aryl boronic acids. See Example 66 and FIG. 14.

DETAILED DESCRIPTION OF THE INVENTION

Ligands of the Present Invention

In certain embodiments, a ligand of the present invention is representedby structure I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer.

In certain embodiments, the ligands of the present invention arerepresented by structure I and the attendant definitions, wherein Rrepresents independently for each occurrence alkyl, cycloalkyl or aryl;at least two instances of R₂ are present; and R₂ is selectedindependently for each occurrence from the group consisting of alkyl andcycloalkyl.

In certain embodiments, a ligand of the present invention is representedby structure II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; and R₂ is absent.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein Rrepresents independently for each occurrence alkyl or cycloalkyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein Rrepresents independently for each occurrence ethyl, cyclohexyl,cyclopropyl, isopropyl or tert-butyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein Rrepresents independently for each occurrence cyclohexyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R′represents independently for each occurrence alkyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R′represents independently for each occurrence isopropyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; R₂ is absent; and R represents independently for each occurrencealkyl or cycloalkyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; R₂ is absent; and R represents independently for each occurrenceethyl, cyclohexyl, cyclopropyl, isopropyl or tert-butyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; R₂ is absent; and R represents independently for each occurrencecyclohexyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; R₂ is absent; R represents independently for each occurrencealkyl or cycloalkyl; and R′ represents independently for each occurrencealkyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; R₂ is absent; R represents independently for each occurrenceethyl, cyclohexyl, cyclopropyl, isopropyl or tert-butyl; and R′represents independently for each occurrence alkyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; R₂ is absent; R represents independently for each occurrencecyclohexyl; and R′ represents independently for each occurrence alkyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; R₂ is absent; R represents independently for each occurrencealkyl or cycloalkyl; and R′ represents independently for each occurrenceisopropyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; R₂ is absent; R represents independently for each occurrenceethyl, cyclohexyl, cyclopropyl, isopropyl or tert-butyl; and R′represents independently for each occurrence isopropyl.

In certain embodiments, the ligands of the present invention arerepresented by structure II and the attendant definitions, wherein R₁ isabsent; R₂ is absent; R represents independently for each occurrencecyclohexyl; and R′ represents independently for each occurrenceisopropyl.

Methods of the Present Invention

In certain embodiments, a method of the present invention is representedby Scheme 5:

wherein

Z is selected from the group consisting of optionally substituted aryl,heteroaryl and alkenyl;

X is selected from the group consisting of Cl, Br, I, —OS(O)₂alkyl, and—OS(O)₂aryl;

R′ and R″ are selected, independently for each occurrence, from thegroup consisting of H, alkyl, heteroalkyl, aryl, formyl, acyl,alkoxycarbonyl, alkylaminocarbonyl, heteroaryl, aralkyl, alkoxyl, amino,trialkylsilyl, and triarylsilyl;

R′ and R″, taken together, may form an optionally substituted ringconsisting of 3-10 backbone atoms inclusive; said ring optionallycomprising one or more heteroatoms beyond the nitrogen to which R′ andR″ are bonded;

R′ and/or R″ may be covalently linked to Z;

the transition metal is selected from the Group 10 metals;

the base is selected from the group consisting of fluorides, hydrides,hydroxides, carbonates, phosphates, alkoxides, metal amides, andcarbanions; and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 1 and the attendant definitions, wherein thetransition metal is palladium.

In certain embodiments, a method of the present invention is representedby Scheme 6:

wherein

Z and Ar′ are independently selected from the group consisting ofoptionally substituted aryl, heteroaryl and alkenyl;

X is selected from the group consisting of Cl, Br, I, —OS(O)₂alkyl, and—OS(O)₂aryl;

Z and Ar′ may be covalently linked;

the transition metal is selected from the Group 10 metals;

the base is selected from the group consisting of fluorides, hydrides,hydroxides, carbonates, phosphates, alkoxides, metal amides, andcarbanions; and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein X is—OS(O)₂aryl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein X is—OS(O)₂tolyl or —OS(O)₂phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein X is—OS(O)₂tolyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein the baseis selected from the group consisting of fluorides, carbonates, andphosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein the baseis cesium fluoride, potassium fluoride, cesium carbonate, or potassiumphosphate.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium; and X is —OS(O)₂aryl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium; and X is —OS(O)₂tolyl or —OS(O)₂phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium; and X is —OS(O)₂tolyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium; X is —OS(O)₂aryl; and the base isselected from the group consisting of fluorides, carbonates, andphosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium; X is —OS(O)₂tolyl or —OS(O)₂phenyl; andthe base is selected from the group consisting of fluorides, carbonates,and phosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium; X is —OS(O)₂tolyl; and the base isselected from the group consisting of fluorides, carbonates, andphosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium; X is —OS(O)₂aryl; and the base is cesiumfluoride, potassium fluoride, cesium carbonate, or potassium phosphate.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium; X is —OS(O)₂tolyl or —OS(O)₂phenyl; andthe base is cesium fluoride, potassium fluoride, cesium carbonate, orpotassium phosphate.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 6 and the attendant definitions, wherein thetransition metal is palladium; X is —OS(O)₂tolyl; and the base is cesiumfluoride, potassium fluoride, cesium carbonate, or potassium phosphate.

In certain embodiments, a method of the present invention is representedby Scheme 7:

wherein

Z is selected from the group consisting of optionally substituted aryl,heteroaryl, and alkenyl;

R is selected from the group consisting of H, alkyl, heteroalkyl,aralkyl, aryl, heteroaryl, alkoxyl, alkylthio, alkylamino, andarylamino;

R′ is selected from the group consisting of H, alkyl, heteroalkyl,aralkyl, aryl, heteroaryl, formyl, acyl, alkoxycarbonyl,alkylaminocarbonyl, and arylaminocarbonyl;

R″ is selected from the group consisting of H, alkyl, heteroalkyl,aralkyl, aryl, and heteroaryl;

X is selected from the group consisting of Cl, Br, I, —OS(O)₂alkyl, and—OS(O)₂aryl;

Z and one of R, R′, and R″ may be covalently linked;

the transition metal is selected from the Group 10 metals;

the base is selected from the group consisting of fluorides, hydrides,hydroxides, carbonates, phosphates, alkoxides, metal amides, andcarbanions; and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 7 and the attendant definitions, wherein thetransition metal is palladium.

In certain embodiments, a method of the present invention is representedby Scheme 8:

wherein

Z and Ar′ are independently selected from the group consisting ofoptionally substituted aryl, heteroaryl and alkenyl;

Ar″ is selected from the group consisting of optionally substitutedaromatic moieties;

Z and Ar′ may be covalently linked;

catalyst consists essentially of at least one palladium atom or ion; andat least one ligand;

the base is selected from the group consisting of fluorides, hydrides,hydroxides, carbonates, phosphates, alkoxides, metal amides, andcarbanions; and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 8 and the attendant definitions, wherein Ar″ istolyl or phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 8 and the attendant definitions, wherein Ar″ istolyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 8 and the attendant definitions, wherein the baseis selected from the group consisting of fluorides, carbonates, andphosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 8 and the attendant definitions, wherein the baseis cesium fluoride, potassium fluoride, cesium carbonate, or potassiumphosphate.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 8 and the attendant definitions, wherein Ar″ istolyl or phenyl; and the base is selected from the group consisting offluorides, carbonates, and phosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 8 and the attendant definitions, wherein Ar″ istolyl or phenyl; and the base is cesium fluoride, potassium fluoride,cesium carbonate, or potassium phosphate.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 8 and the attendant definitions, wherein Ar″ istolyl; and the base is selected from the group consisting of fluorides,carbonates, and phosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 8 and the attendant definitions, wherein Ar″ istolyl; and the base is cesium fluoride, potassium fluoride, cesiumcarbonate, or potassium phosphate.

In certain embodiments, a method of the present invention is representedby Scheme 9:

wherein

Z is selected from the group consisting of optionally substituted aryl,heteroaryl and alkenyl;

Ar″ is selected from the group consisting of optionally substitutedaromatic moieties;

R is selected from the group consisting of H, alkyl, heteroalkyl,aralkyl, aryl, heteroaryl, alkoxyl, alkylthio, alkylamino, andarylamino;

R′ is selected from the group consisting of H, alkyl, heteroalkyl,aralkyl, aryl, heteroaryl, formyl, acyl, alkoxycarbonyl,alkylaminocarbonyl, and arylaminocarbonyl;

R″ is selected from the group consisting of H, alkyl, heteroalkyl,aralkyl, aryl, and heteroaryl;

Z and one of R, R′, and R″ may be covalently linked;

catalyst consists essentially of at least one palladium atom or ion; andat least one ligand;

the base is selected from the group consisting of fluorides, hydrides,hydroxides, carbonates, phosphates, alkoxides, metal amides, andcarbanions; and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 9 and the attendant definitions, wherein Ar″ istolyl or phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 9 and the attendant definitions, wherein Ar″ isphenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 9 and the attendant definitions, wherein the baseis selected from the group consisting of fluorides, carbonates, andphosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 9 and the attendant definitions, wherein the baseis cesium fluoride, potassium fluoride, cesium carbonate, or potassiumphosphate.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 9 and the attendant definitions, wherein Ar″ istolyl or phenyl; and the base is selected from the group consisting offluorides, carbonates, and phosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 9 and the attendant definitions, wherein Ar″ istolyl or phenyl; and the base is cesium fluoride, potassium fluoride,cesium carbonate, or potassium phosphate.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 9 and the attendant definitions, wherein Ar″ isphenyl; and the base is selected from the group consisting of fluorides,carbonates, and phosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 9 and the attendant definitions, wherein Ar″ isphenyl; and the base is cesium fluoride, potassium fluoride, cesiumcarbonate, or potassium phosphate.

In certain embodiments, a method of the present invention is representedby Scheme 10:

wherein

Z is selected from the group consisting of optionally substituted aryl,heteroaryl and alkenyl;

X is selected from the group consisting of Cl, Br, I, —OS(O)₂alkyl, and—OS(O)₂aryl;

R′ and R″ are selected, independently for each occurrence, from thegroup consisting of H, alkyl, heteroalkyl, aryl, formyl, acyl,alkoxycarbonyl, alkylaminocarbonyl, heteroaryl, aralkyl, alkoxyl, amino,trialkylsilyl, and triarylsilyl;

R′ and R″, taken together, may form an optionally substituted ringconsisting of 3-10 backbone atoms inclusive; said ring optionallycomprising one or more heteroatoms beyond the nitrogen to which R′ andR″ are bonded;

R′ and/or R″ may be covalently linked to Z;

catalyst consists essentially of at least one palladium atom or ion; andat least one ligand;

solvent is water;

the base is selected from the group consisting of fluorides, hydroxides,carbonates, phosphates, and alkoxides; and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of carbonates and hydroxides.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydroxide and potassium hydroxide.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of potassium carbonate, sodiumhydroxide and potassium hydroxide.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein X is Cl,Br or I.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein X is Clor Br.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein X is Cl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein Z isoptionally substituted phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of carbonates and hydroxides; andX is Cl, Br or I.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of carbonates and hydroxides; X isCl, Br or I; and Z is optionally substituted phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of carbonates and hydroxides; andX is Cl or Br.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of carbonates and hydroxides; X isCl or Br; and Z is optionally substituted phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of carbonates and hydroxides; andX is Cl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of carbonates and hydroxides; X isCl; and Z is optionally substituted phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of potassium carbonate, sodiumhydroxide, and potassium hydroxide; X is Cl, Br, or I; and Z isoptionally substituted phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of potassium carbonate, sodiumhydroxide, and potassium hydroxide; X is Cl or Br; and Z is optionallysubstituted phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 10 and the attendant definitions, wherein the baseis selected from the group consisting of potassium carbonate, sodiumhydroxide, and potassium hydroxide; X is Cl; and Z is optionallysubstituted phenyl.

In certain embodiments, a method of the present invention is representedby Scheme 11:

wherein

Z is selected from the group consisting of optionally substituted aryl,heteroaryl and alkenyl;

X is selected from the group consisting of Cl, Br, I, —OS(O)₂alkyl, and—OS(O)₂aryl;

R′ and R″ are selected, independently for each occurrence, from thegroup consisting of H, alkyl, heteroalkyl, aryl, formyl, acyl,alkoxycarbonyl, alkylaminocarbonyl, heteroaryl, aralkyl, alkoxyl, amino,trialkylsilyl, and triarylsilyl;

R′ and R″, taken together, may form an optionally substituted ringconsisting of 3-10 backbone atoms inclusive; said ring optionallycomprising one or more heteroatoms beyond the nitrogen to which R′ andR″ are bonded;

R′ and/or R″ may be covalently linked to Z;

catalyst consists essentially of at least one palladium atom or ion; andat least one ligand;

solvent comprises a hydroxylic solvent in greater than 50% by volume;

the base is selected from the group consisting of fluorides, hydroxides,carbonates, phosphates, and alkoxides; and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is a lower alkyl alcohol.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is tert-butanol.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidsolvent consists essentially of said hydroxylic solvent.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein the baseis selected from the group consisting of alkoxides, carbonates,phosphates and hydroxides.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein the baseis selected from the group consisting of sodium phosphate, potassiumphosphate, sodium tert-butoxide, potassium tert-butoxide, sodiumcarbonate, potassium carbonate, sodium hydroxide and potassiumhydroxide.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein X is Clor Br.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein Z isoptionally substituted phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is a lower alkyl alcohol; and said solvent consistsessentially of said hydroxylic solvent.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is tert-butanol; and said solvent consistsessentially of said hydroxylic solvent.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is a lower alkyl alcohol; said solvent consistsessentially of said hydroxylic solvent; and the base is selected fromthe group consisting of alkoxides, carbonates, phosphates andhydroxides.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is a lower alkyl alcohol; said solvent consistsessentially of said hydroxylic solvent; the base is selected from thegroup consisting of alkoxides, carbonates, phosphates and hydroxides;and X is Cl or Br.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is a lower alkyl alcohol; said solvent consistsessentially of said hydroxylic solvent; the base is selected from thegroup consisting of alkoxides, carbonates, phosphates and hydroxides; Xis Cl or Br; and Z is optionally substituted phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is tert-butanol; said solvent consists essentially ofsaid hydroxylic solvent; and the base is selected from the groupconsisting of sodium phosphate, potassium phosphate, sodiumtert-butoxide, potassium tertbutoxide, sodium carbonate, potassiumcarbonate, sodium hydroxide and potassium hydroxide.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is tert-butanol; said solvent consists essentially ofsaid hydroxylic solvent; the base is selected from the group consistingof sodium phosphate, potassium phosphate, sodium tert-butoxide,potassium tert-butoxide, sodium carbonate, potassium carbonate, sodiumhydroxide and potassium hydroxide; and X is Cl or Br.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 11 and the attendant definitions, wherein saidhydroxylic solvent is tert-butanol; said solvent consists essentially ofsaid hydroxylic solvent; the base is selected from the group consistingof sodium phosphate, potassium phosphate, sodium tert-butoxide,potassium tert-butoxide, sodium carbonate, potassium carbonate, sodiumhydroxide and potassium hydroxide; X is Cl or Br; and Z is optionallysubstituted phenyl.

In certain embodiments, a method of the present invention is representedby Scheme 12:

wherein

Z is selected from the group consisting of optionally substitutedmonocyclic and polycyclic aromatic and heteroaromatic moieties;

Ar″ is selected from the group consisting of optionally substitutedaromatic moieties;

R is selected from the group consisting of optionally substituted alkyland aralkyl;

R′ is selected, independently for each occurrence, from the groupconsisting of alkyl and heteroalkyl; the carbon-boron bond of said alkyland heteroalkyl groups being inert under the reaction conditions; B(R′)₂taken together may represent 9-borobicyclo[3.3.1]nonyl.

Z and R may be covalently linked;

catalyst consists essentially of at least one palladium atom or ion; andat least one ligand;

the base is selected from the group consisting of fluorides, hydrides,hydroxides, carbonates, phosphates, alkoxides, metal amides, andcarbanions; and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 12 and the attendant definitions, wherein Ar″ istolyl or phenyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 12 and the attendant definitions, wherein the baseis selected from the group consisting of fluorides, carbonates, andphosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 12 and the attendant definitions, wherein the baseis cesium fluoride, potassium fluoride, cesium carbonate, or potassiumphosphate.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 12 and the attendant definitions, wherein B(R′)₂taken together represents 9-borobicyclo[3.3.1]nonyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 12 and the attendant definitions, wherein Ar″ istolyl or phenyl; and the base is selected from the group consisting offluorides, carbonates, and phosphates.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 12 and the attendant definitions, wherein Ar″ istolyl or phenyl; and the base is cesium fluoride, potassium fluoride,cesium carbonate, or potassium phosphate.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 12 and the attendant definitions, wherein Ar″ istolyl or phenyl; the base is selected from the group consisting offluorides, carbonates, and phosphates; and B(R′)₂ taken togetherrepresents 9-borobicyclo[3.3.1]nonyl.

In certain embodiments, the present invention relates to the methodrepresented by Scheme 12 and the attendant definitions, wherein Ar″ istolyl or phenyl; the base is cesium fluoride, potassium fluoride, cesiumcarbonate, or potassium phosphate; and B(R′)₂ taken together represents9-borobicyclo[3.3.1]nonyl.

In certain embodiments, a method of the present invention is representedby Scheme 13:

wherein

Ar is selected from the group consisting of optionally substitutedmonocyclic and polycyclic aromatic and heteroaromatic moieties;

X is selected from the group consisting of Cl, Br, I, —OS(O)₂alkyl, and—OS(O)₂aryl;

R′ and R″ are selected, independently for each occurrence, from thegroup consisting of H, alkyl, heteroalkyl, aryl, heteroaryl, aralkyl,alkoxyl, amino, trialkylsilyl, and triarylsilyl;

R′ and R″, taken together, may form an optionally substituted ringconsisting of 3-10 backbone atoms inclusive; said ring optionallycomprising one or more heteroatoms beyond the nitrogen to which R′ andR″ are bonded;

R′ and/or R″ may be covalently linked to Ar;

the transition metal is selected from the group 8-10 metals;

the base is selected from the group consisting of hydrides, hydroxides,carbonates, phosphates, alkoxides, amides, carbanions, and silyl anions;and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.

In certain embodiments, a method of the present invention is representedby Scheme 14:

wherein

Ar and Ar′ are independently selected from the group consisting ofoptionally substituted monocyclic and polycyclic aromatic andheteroaromatic moieties;

X is selected from the group consisting of Cl, Br, I, —OS(O)₂alkyl, and—OS(O)₂aryl;

Ar and Ar′ may be covalently linked;

the transition metal is selected from the group 8-10 metals;

the base is selected from the group consisting of hydrides, hydroxides,carbonates, phosphates, alkoxides, amides, carbanions, and silyl anions;and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.

In certain embodiments, a method of the present invention is representedby Scheme 15:

wherein

Ar is selected from the group consisting of optionally substitutedmonocyclic and polycyclic aromatic and heteroaromatic moieties;

R is selected from the group consisting of optionally substituted alkyl,heteroalkyl, and aralkyl;

R′ is selected, independently for each occurrence, from the groupconsisting of alkyl and heteroalkyl; the carbon-boron bond of said alkyland heteroalkyl groups being inert under the reaction conditions; BR′₂taken together may represent 9-borobicyclo[3.3.1]nonyl.

X is selected from the group consisting of Cl, Br, I, —OS(O)₂alkyl, and—OS(O)₂aryl;

Ar and R may be covalently linked;

the transition metal is selected from the group 8-10 metals;

the base is selected from the group consisting of hydrides, hydroxides,carbonates, phosphates, alkoxides, amides, carbanions, and silyl anions;and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.

In certain embodiments, a method of the present invention is representedby Scheme 16:

wherein

Ar is selected from the group consisting of optionally substitutedmonocyclic and polycyclic aromatic and heteroaromatic moieties;

R, R′, and R″ are selected, independently for each occurrence, from thegroup consisting of H, alkyl, heteroalkyl, aralkyl, aryl, heteroaryl;

X is selected from the group consisting of Cl, Br, I, —OS(O)₂alkyl, and—OS(O)₂aryl;

Ar and one of R, R′, and R″ may be covalently linked;

the transition metal is selected from the group 8-10 metals;

the base is selected from the group consisting of hydrides, hydroxides,carbonates, phosphates, alkoxides, amides, carbanions, and silyl anions;and

the ligand is selected from the group consisting of:

compounds represented by I:

wherein

R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, —SiR₃, and —(CH₂)_(m)—R₈₀;

R₈₀ represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and

the ligand, when chiral, is a mixture of enantiomers or a singleenantiomer; and compounds represented by II:

wherein

R and R′ are selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀;

the A and A′ rings of the biphenyl core independently may beunsubstituted or substituted with R₁ and R₂, respectively, any number oftimes up to the limitations imposed by stability and the rules ofvalence;

R₁ and R₂, when present, are selected independently for each occurrencefrom the group consisting of alkyl, cycloalkyl, halogen, —SiR₃, and—(CH₂)_(m)—R₈₀;

R₈₀ represents independently for each occurrence cycloalkyl or aryl;

m is independently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.

In certain embodiments, the present invention relates to a methodrepresented by any of the aforementioned Schemes that provides theproduct in a yield of greater than 50%; in more preferred embodiments,the product is provided in a yield of greater than 70%; and in the mostpreferred embodiments, the product is provided in a yield of greaterthan 85%.

In certain embodiments, the present invention relates to a methodrepresented by any of the aforementioned Schemes, wherein the transitionmetal and ligand are selected to provide the product at roomtemperature.

In certain embodiments, the present invention relates to a methodrepresented by any of the aforementioned Schemes, wherein the transitionmetal and ligand are selected to provide the product when X is chloride.

In certain embodiments, the present invention relates to a methodrepresented by any of the aforementioned Schemes, wherein the transitionmetal and ligand are selected to provide the product utilizing less than0.01 mol % of the catalyst relative to the limiting reagent.

In certain embodiments, the present invention relates to a methodrepresented by any of the aforementioned Schemes, wherein the transitionmetal and ligand are selected to provide the product utilizing less than0.0001 mol % of the catalyst relative to the limiting reagent.

In certain embodiments, the present invention relates to a methodrepresented by any of the aforementioned Schemes, wherein the transitionmetal and ligand are selected to consume the limiting reagent in lessthan 48 hours.

In certain embodiments, the present invention relates to a methodrepresented by any of the aforementioned Schemes, wherein the transitionmetal and ligand are selected to consume the limiting reagent in lessthan 24 hours.

In certain embodiments, the present invention relates to a methodrepresented by any of the aforementioned Schemes, wherein the transitionmetal and ligand are selected to consume the limiting reagent in lessthan 12 hours.

Various General Considerations

In preferred embodiments of the reactions of the invention, there is noneed to use large excesses of reactants, e.g., amine, boronic acid,ketone and the like, or aromatic compound. The reactions proceed quicklyand in high yield to the desired products using substantiallystoichiometric amounts of reagents. For example, in the aminationreactions of the invention, the amine may be present in as little as atwo-fold excess and preferably in no greater than a 20% excess relativeto the aromatic compound. Alternatively, the aromatic compound may bepresent in as little as a two-fold excess and preferably in no greaterthan a 20% excess relative to the amine. An analogous discussion appliesto the subject Suzuki couplings and α-arylations.

The reactions typically proceed at mild temperatures and pressures togive high yields of the product aryl amines, biaryls, α-aryl ketones,and the like. Thus, yields of desired products greater than 45%,preferably greater than 75%, and even more preferably greater than 80%,may be obtained from reactions at mild temperatures according to theinvention. The reaction may be carried out at temperature less than 120°C., and preferably in the range of 20-100° C. In certain preferredembodiments, the reactions are carried out at ambient temperature.

The reactions can be run in a wide range of solvent systems, includingpolar aprotic solvents. Alternatively, in certain embodiments, thesubject reactions may be carried in the absence of added solvent.

The ability to provide synthesis schemes for aryl amines, biaryls,α-aryl ketones, and the like, which can be carried out under mildconditions and/or with non-polar solvents has broad application,especially in the agricultural and pharmaceutical industries, as well asin the polymer industry. In this regard, the subject reactions areparticularly well-suited to reactants or products which includesensitive functionalities, e.g., which would otherwise be labile underharsh reaction conditions.

The subject amine arylation, Suzuki coupling, ketone α-arylationreactions and the like can be used as part of combinatorial synthesisschemes to yield libraries of aryl amines, biaryls, α-aryl ketones, andthe like. Accordingly, another aspect of the present invention relatesto use of the subject method to generate variegated libraries of arylamines, biaryls, α-aryl ketones, and the like, and to the librariesthemselves. The libraries can be soluble or linked to insolublesupports, e.g., through a substituent of a reactant (prior to carryingout a reaction of the present invention), e.g., the aryl group, amine,boronic acid, ketone, or the like, or through a substituent of a product(subsequent to carrying out a reaction of the present invention), e.g.,the aryl amine, biaryl, α-aryl ketone, or the like.

The ligands of the present invention and the methods based thereonenable the formation of carbon-heteroatom and carbon-carbon bonds—viatransition metal catalyzed aminations, Suzuki couplings, α-arylations ofcarbonyls, and the like—under conditions that would not yieldappreciable amounts of the observed product(s) using ligands and methodsknown in the art. In preferred embodiments, the ligands and methods ofthe present invention catalyze the aforementioned transformations attemperatures below 50° C., and in certain embodiments they occur at roomtemperature. When a reaction is said to occur under a given set ofconditions it means that the rate of the reaction is such the bulk ofthe starting materials is consumed, or a significant amount of thedesired product is produced, within 48 hours, and preferably within 24hours, and most preferably within 12 hours. In certain embodiments, theligands and methods of the present invention catalyze the aforementionedtransformations utilizing less than 1 mol % of the catalyst complexrelative to the limiting reagent, in certain preferred embodiments lessthan 0.01 mol % of the catalyst complex relative to the limitingreagent, and in additional preferred embodiments less than 0.0001 mol %of the catalyst complex relative to the limiting reagent.

The ligands of the present invention and the methods based thereon canbe used to produce synthetic intermediates that, after being subjectedto additional methods known in the art, are transformed to desired endproducts, e.g., lead compounds in medicinal chemistry programs,pharmaceuticals, insecticides, antivirals and antifungals. Furthermore,the ligands of the present invention and the methods based thereon maybe used to increase the efficiency of and/or shorten established routesto desired end products, e.g., lead compounds in medicinal chemistryprograms, pharmaceuticals, insecticides, antivirals and antifungals.

II. Definitions

For convenience, before further description of the present invention,certain terms employed in the specification, examples, and appendedclaims are collected here.

The terms “biphenyl” and “binaphthylene” refer to the ring systemsbelow. The numbers around the peripheries of the ring systems are thepositional numbering systems used herein. Likewise, the capital letterscontained within the individual rings of the ring systems are the ringdescriptors used herein.

The term “substrate aryl group” refers to an aryl group containing anelectrophilic atom which is susceptible to the subject cross-couplingreaction, e.g., the electrophilic atom bears a leaving group. Inreaction scheme 1, the substrate aryl is represented by ArX, and X isthe leaving group. The aryl group, Ar, is said to be substituted if, inaddition to X, it is substituted at yet other positions. The substratearyl group can be a single ring molecule, or can be a component of alarger molecule.

The term “nucleophile” is recognized in the art, and as used hereinmeans a chemical moiety having a reactive pair of electrons.

The term “electrophile” is art-recognized and refers to chemicalmoieties which can accept a pair of electrons from a nucleophile asdefined above. Electrophilic moieties useful in the method of thepresent invention include halides and sulfonates.

The terms “electrophilic atom”, “electrophilic center” and “reactivecenter” as used herein refer to the atom of the substrate aryl moietywhich is attacked by, and forms a new bond to the nucleophilicheteroatom of the hydrazine and the like. In most (but not all) cases,this will also be the aryl ring atom from which the leaving groupdeparts.

The term “electron-withdrawing group” is recognized in the art, anddenotes the tendency of a substituent to attract valence electrons fromneighboring atoms, i.e., the substituent is electronegative with respectto neighboring atoms. A quantification of the level ofelectron-withdrawing capability is given by the Hammett sigma (s)constant. This well known constant is described in many references, forinstance, J. March, Advanced Organic Chemistry, McGraw Hill BookCompany, New York, (1977 edition) pp. 251-259. The Hammett constantvalues are generally negative for electron donating groups (s[P]=−0.66for NH₂) and positive for electron withdrawing groups (s[P]=0.78 for anitro group), s[P] indicating para substitution. Exemplaryelectron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl,trifluoromethyl, —CN, chloride, and the like. Exemplaryelectron-donating groups include amino, methoxy, and the like.

The term “reaction product” means a compound which results from thereaction of the hydrazine or the like and the substrate aryl group. Ingeneral, the term “reaction product” will be used herein to refer to astable, isolable aryl ether adduct, and not to unstable intermediates ortransition states.

The term “catalytic amount” is recognized in the art and means asubstoichiometric amount of reagent relative to a reactant. As usedherein, a catalytic amount means from 0.0001 to 90 mole percent reagentrelative to a reactant, more preferably from 0.001 to 50 mole percent,still more preferably from 0.01 to 10 mole percent, and even morepreferably from 0.1 to 5 mole percent reagent to reactant.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branchedchain), and more preferably 20 or fewer. Likewise, preferred cycloalkylshave from 3-10 carbon atoms in their ring structure, and more preferablyhave 5, 6 or 7 carbons in the ring structure.

Moreover, the term “alkyl” (or “lower alkyl”) as used throughout thespecification and claims is intended to include both “unsubstitutedalkyls” and “substituted alkyls”, the latter of which refers to alkylmoieties having substituents replacing a hydrogen on one or more carbonsof the hydrocarbon backbone. Such substituents can include, for example,a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an ester, aformyl, or a ketone), a thiocarbonyl (such as a thioester, athioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate,a phosphinate, an amino, an amido, an amidine, an imine, a cyano, anitro, an azido, a sulfhydryl, an a lkylthio, a sulfate, a sulfonate, asulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or anaromatic or heteroaromatic moiety. It will be understood by thoseskilled in the art that the moieties substituted on the hydrocarbonchain can themselves be substituted, if appropriate. For instance, thesubstituents of a substituted alkyl may include substituted andunsubstituted forms of amino, azido, imino, amido, phosphoryl (includingphosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido,sulfamoyl and sulfonate), and silyl groups, as well as ethers,alkylthios, carbonyls (including ketones, aldehydes, carboxylates, andesters), —CF₃, —CN and the like. Exemplary substituted alkyls aredescribed below. Cycloalkyls can be further substituted with alkyls,alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls,—CF₃, —CN, and the like.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group (e.g., an aromatic or heteroaromatic group).

The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groupsanalogous in length and possible substitution to the alkyls describedabove, but that contain at least one double or triple bond respectively.

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths. Preferred alkyl groups are lower alkyls. Inpreferred embodiments, a substituent designated herein as alkyl is alower alkyl.

The term “aryl” as used herein includes 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, naphthalene, anthracene, pyrene,pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole,pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.Those aryl groups having heteroatoms in the ring structure may also bereferred to as “aryl heterocycles” or “heteroaromatics”. The aromaticring can be substituted at one or more ring positions with suchsubstituents as described above, for example, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,heterocyclyl, aromatic or heteroaromatic moieties, —CF₃, —CN, or thelike. The term “aryl” also includes polycyclic ring systems having twoor more cyclic rings in which two or more carbons are common to twoadjoining rings (the rings are “fused rings”) wherein at least one ofthe rings is aromatic, e.g., the other cyclic rings can be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms, and dba represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl, methanesulfonyl, and dibenzylideneacetone,respectively. A more comprehensive list of the abbreviations utilized byorganic chemists of ordinary skill in the art appears in the first issueof each volume of the Journal of Organic Chemistry; this list istypically presented in a table entitled Standard List of Abbreviations.The abbreviations contained in said list, and all abbreviations utilizedby organic chemists of ordinary skill in the art are hereby incorporatedby reference.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstitutedbenzenes, respectively. For example, the names 1,2-dimethylbenzene andortho-dimethylbenzene are synonymous.

The terms “heterocyclyl” or “heterocyclic group” refer to 3- to10-membered ring structures, more preferably 3- to 7-membered rings,whose ring structures include one to four heteroatoms. Heterocycles canalso be polycycles. Heterocyclyl groups include, for example, thiophene,thianthrene, furan, pyran, isobenzofuran, chromene, xanthene,phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,indole, indazole, purine, quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine,piperazine, morpholine, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. The heterocyclic ringcan be substituted at one or more positions with such substituents asdescribed above, as for example, halogen, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic orheteroaromatic moiety, —CF₃, —CN, or the like.

The terms “polycyclyl” or “polycyclic group” refer to two or more rings(e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle can be substituted with such substituents as described above,as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromaticmoiety, —CF₃, —CN, or the like.

The term “carbocycle”, as used herein, refers to an aromatic ornon-aromatic ring in which each atom of the ring is carbon.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen,sulfur and phosphorous.

As used herein, the term “nitro” means —NO₂; the term “halogen”designates —F, —Cl, —Br or —I; the term “sulfhydryl” means —SH; the term“hydroxyl” means —OH; and the term “sulfonyl” means —SO₂—.

The terms “amine” and “amino” are art recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that can berepresented by the general formula:

wherein R₉, R₁₀ and R′₁₀ each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)—R₈, or R₉ and R₁₀ taken together with theN atom to which they are attached complete a heterocycle having from 4to 8 atoms in the ring structure; R₈ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. In preferred embodiments, only one of R₉ or R₁₀can be a carbonyl, e.g., R₉, R₁₀ and the nitrogen together do not forman imide. In even more preferred embodiments, R₉ and R₁₀ (and optionallyR′₁₀) each independently represent a hydrogen, an alkyl, an alkenyl, or—(CH₂)_(m)—R₈. Thus, the term “alkylamine” as used herein means an aminegroup, as defined above, having a substituted or unsubstituted alkylattached thereto, i.e., at least one of R₉ and R₁₀ is an alkyl group.

The term “acylamino” is art-recognized and refers to a moiety that canbe represented by the general formula:

wherein R₉ is as defined above, and R′₁₁ represents a hydrogen, analkyl, an alkenyl or —(CH₂)_(m)—R₈, where m and R₈ are as defined above.

The term “amido” is art recognized as an amino-substituted carbonyl andincludes a moiety that can be represented by the general formula:

wherein R₉, R₁₀ are as defined above. Preferred embodiments of the amidewill not include imides which may be unstable.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In preferred embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl,—S-alkynyl, and —S—(CH₂)_(m)—R₈, wherein m and R₈ are defined above.Representative alkylthio groups include methylthio, ethyl thio, and thelike.

The term “carbonyl” is art recognized and includes such moieties as canbe represented by the general formula:

wherein X is a bond or represents an oxygen or a sulfur, and R₁₁represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R₈ or apharmaceutically acceptable salt, R′₁₁ represents a hydrogen, an alkyl,an alkenyl or —(CH₂)_(m)—R₈, where m and R₈ are as defined above. WhereX is an oxygen and R₁₁ or R′₁₁ is not hydrogen, the formula representsan “ester”. Where X is an oxygen, and R₁₁ is as defined above, themoiety is referred to herein as a carboxyl group, and particularly whenR₁₁ is a hydrogen, the formula represents a “carboxylic acid”. Where Xis an oxygen, and R′₁₁ is hydrogen, the formula represents a “formate”.In general, where the oxygen atom of the above formula is replaced bysulfur, the formula represents a “thiolcarbonyl” group. Where X is asulfur and R₁₁ or R′₁₁ is not hydrogen, the formula represents a“thiolester.” Where X is a sulfur and R₁₁ is hydrogen, the formularepresents a “thiolcarboxylic acid.” Where X is a sulfur and R₁₁′ ishydrogen, the formula represents a “thiolformate.” On the other hand,where X is a bond, and R₁₁ is not hydrogen, the above formula representsa “ketone” group. Where X is a bond, and R₁₁ is hydrogen, the aboveformula represents an “aldehyde” group.

The terms “alkoxyl” or “alkoxy” as used herein refers to an alkyl group,as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as can berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH₂)_(m)—R₈,where m and R₈ are described above.

The term “sulfonate” is art recognized and includes a moiety that can berepresented by the general formula:

in which R₄₁ is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The term “sulfate” is art recognized and includes a moiety that can berepresented by the general formula:

in which R₄₁ is as defined above.

The term “sulfonamido” is art recognized and includes a moiety that canbe represented by the general formula:

in which R₉ and R′₁₁ are as defined above.

The term “sulfamoyl” is art-recognized and includes a moiety that can berepresented by the general formula:

in which R₉ and R₁₀ are as defined above.

The terms “sulfoxido” or “sulfinyl”, as used herein, refers to a moietythat can be represented by the general formula:

in which R₄₄ is selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

A “phosphoryl” can in general be represented by the formula:

wherein Q₁ represented S or O, and R₄₆ represents hydrogen, a loweralkyl or an aryl. When used to substitute, e.g., an alkyl, thephosphoryl group of the phosphorylalkyl can be represented by thegeneral formula:

wherein Q₁ represented S or O, and each R₄₆ independently representshydrogen, a lower alkyl or an aryl, Q₂ represents O, S or N. When Q₁ isan S, the phosphoryl moiety is a “phosphorothioate”.

A “phosphoramidite” can be represented in the general formula:

wherein R₉ and R₁₀ are as defined above, and Q₂ represents O, S or N.

A “phosphonamidite” can be represented in the general formula:

wherein R₉ and R₁₀ are as defined above, Q₂ represents O, S or N, andR₄₈ represents a lower alkyl or an aryl, Q₂ represents O, S or N.

A “selenoalkyl” refers to an alkyl group having a substituted selenogroup attached thereto. Exemplary “selenoethers” which may besubstituted on the alkyl are selected from one of —Se-alkyl,—Se-alkenyl, —Se-alkynyl, and —Se—(CH₂)_(m)—R₈, m and R₈ being definedabove.

Analogous substitutions can be made to alkenyl and alkynyl groups toproduce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls.

The phrase “protecting group” as used herein means temporarymodifications of a potentially reactive functional group which protectit from undesired chemical transformations. Examples of such protectinggroups include esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991).

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described hereinabove. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this invention, the heteroatoms such asnitrogen may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalencies of the heteroatoms. This invention is not intended to belimited in any manner by the permissible substituents of organiccompounds.

A “polar solvent” means a solvent which has a dielectric constant (∈) of2.9 or greater, such as DMF, THF, ethylene glycol dimethyl ether (DME),DMSO, acetone, acetonitrile, methanol, ethanol, isopropanol, n-propanol,t-butanol or 2-methoxyethyl ether. Preferred polar solvents are DMF,DME, NMP, and acetonitrile.

An “aprotic solvent” means a non-nucleophilic solvent having a boilingpoint range above ambient temperature, preferably from about 25° C. toabout 190° C., more preferably from about 80° C. to about 160° C., mostpreferably from about 80° C. to 150° C., at atmospheric pressure.Examples of such solvents are acetonitrile, toluene, DMF, diglyme, THFor DMSO.

A “polar, aprotic solvent” means a polar solvent as defined above whichhas no available hydrogens to exchange with the compounds of thisinvention during reaction, for example DMF, acetonitrile, diglyme, DMSO,or THF.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Alsofor purposes of this invention, the term “hydrocarbon” is contemplatedto include all permissible compounds having at least one hydrogen andone carbon atom. In a broad aspect, the permissible hydrocarbons includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and nonaromatic organic compounds which can besubstituted or unsubstituted.

III. Exemplary Catalyzed Reactions

As described above, one invention of the Applicants' features atransition metal-catalyzed amination reaction which comprises combiningan amine with a substrate aryl group bearing an activated group X. Thereaction includes at least a catalytic amount of a transition metalcatalyst, comprising a novel ligand, and the combination is maintainedunder conditions appropriate for the metal catalyst to catalyze thearylation of the amine.

The two ligands (24 and 25) shown below are referred to by number in theillustrative embodiments in this section.

In an illustrative embodiment, the subject methods can be used for theintermolecular reaction between an electron-rich aryl chloride andpyrrolidine to give an N-aryl pyrrolidine:

In a second illustrative embodiment, the subject methods can be used toachieve the N-arylation of indole with an electron-rich aryl bromide:

Another aspect of the present invention involves the catalysis by Pd/4of the amination of electron-poor aryl chlorides, as depicted in thefollowing illustrative transformation.

An additional aspect of the present invention centers on the roomtemperature amination of aryl iodides or bromides, as depicted in thefollowing illustrative transformation involving an aryl iodide.

In another illustrative embodiment, the subject methods are exploited ina palladium-catalyzed amination of an electron-neutral aryl chloride.

One of ordinary skill in the art will be able to envision intramolecularvariants of the subject amination methods. An illustrative embodimentfollows:

Another aspect of the Applicants' invention features a transitionmetal-catalyzed Suzuki cross-coupling reaction between an arylboronicacid, arylboronic ester, alkylborane, or the like and a substrate arylbearing an activated group X. The reaction includes at least a catalyticamount of a transition metal catalyst, comprising a novel ligand, andthe combination is maintained under conditions appropriate for the metalcatalyst to catalyze the cross-coupling reaction between theboron-containing reactant and the substrate aryl reactant.

In an embodiment illustrative of the Suzuki coupling aspect of theinvention, the subject methods may be exploited in the preparation of3,5-dimethoxybiphenyl, at room temperature, from1-chloro-3,5-dimethoxybenzene and phenylboronic acid:

In an second embodiment illustrative of the Suzuki coupling aspect ofthe invention, the subject methods may be exploited in the formation ofa sp²-sp³ carbon-carbon bond; an electron-rich aryl chloride reacts withan alkyl borane to give an alkylarene:

One of ordinary skill in the art will be able to envision intramolecularvariants of the subject Suzuki coupling methods. An illustrativeembodiment follows:

Still another aspect of the Applicants' invention features a transitionmetal-catalyzed α-arylation of ketones involving the reaction of anenolizable ketone with a substrate aryl bearing an activated group X.The reaction includes at least a catalytic amount of a transition metalcatalyst, comprising a novel ligand, and the combination is maintainedunder conditions appropriate for the metal catalyst to catalyze theα-arylation of the enolizable ketone.

In an embodiment illustrative of the α-arylation aspect of theinvention, the subject methods may be exploited in the preparation of6-methyl-2-(3,4-dimethylphenyl)cyclohexanone, at room temperature, from1-bromo-3,4-dimethylbenzene and 2-methylcyclohexanone:

One of ordinary skill in the art will be able to envision intramolecularvariants of the subject α-arylation methods. An illustrative embodimentfollows:

The substrate aryl compounds include compounds derived from simplearomatic rings (single or polycylic) such as benzene, naphthalene,anthracene and phenanthrene; or heteroaromatic rings (single orpolycyclic), such as pyrrole, thiophene, thianthrene, furan, pyran,isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole,pyrazole, thiazole, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, perimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,thiolane, oxazole, piperidine, piperazine, morpholine and the like. Inpreferred embodiment, the reactive group, X, is substituted on a five,six or seven membered ring (though it can be part of a largerpolycycle).

In preferred embodiments, the aryl substrate may be selected from thegroup consisting of phenyl and phenyl derivatives, heteroaromaticcompounds, polycyclic aromatic and heteroaromatic compounds, andfunctionalized derivatives thereof. Suitable aromatic compounds derivedfrom simple aromatic rings and heteroaromatic rings, include but are notlimited to, pyridine, imidizole, quinoline, furan, pyrrole, thiophene,and the like. Suitable aromatic compounds derived from fused ringsystems, include but are not limited to naphthalene, anthracene,tetralin, indole and the like.

Suitable aromatic compounds may have the formula Z_(p)ArX, where X is anactivated substituent. An activated substituent, X, is characterized asbeing a good leaving group. In general, the leaving group is a groupsuch as a halide or sulfonate. Suitable activated substituents include,by way of example only, halides such as chloride, bromide and iodide,and sulfonate esters such as triflate, mesylate, nonaflate and tosylate.In certain embodiments, the leaving group is a halide selected fromiodine, bromine, and chlorine.

Z represents one or more optional substituents on the aromatic ring,though each occurence of Z (p>1) is independently selected. By way ofexample only, each incidence of substitution independently can be, asvalence and stability permit, a halogen, a lower alkyl, a lower alkenyl,a lower alkynyl, a carbonyl (e.g., an ester, a carboxylate, or aformate), a thiocarbonyl (e.g., a thiolester, a thiolcarboxylate, or athiolformate), a ketyl, an aldehyde, an amino, an acylamino, an amido,an amidino, a cyano, a nitro, an azido, a sulfonyl, a sulfoxido, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, aphosphonate, a phosphinate, —(CH₂)_(m)—R₈, —(CH₂)_(m)—OH,—(CH₂)_(m)—O-lower alkyl, —(CH₂)_(m)—O-lower alkenyl,—(CH₂)_(m)—O—(CH₂)_(n)—R₈, —(CH₂)_(m)—SH, —(CH₂)_(m)—S-lower alkyl,—(CH₂)_(m)—S-lower alkenyl, —(CH₂)_(m)—S—(CH₂)_(n)—R₈, or protectinggroups of the above or a solid or polymeric support; R₈ represents asubstituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, orheterocycle; and n and m are independently for each occurrence zero oran integer in the range of 1 to 6. P is preferably in the range of 0 to5. For fused rings, where the number of substitution sites on the arylgroup increases, p may be adjusted appropriately.

In certain embodiments, suitable substituents Z include alkyl, aryl,acyl, heteroaryl, amino, carboxylic ester, carboxylic acid, hydrogen,ether, thioether, amide, carboxamide, nitro, phosphonic acid, hydroxyl,sulfonic acid, halide, pseudohalide groups, and substituted derivativesthereof, and p is in the range of 0 to 5. In particular, the reaction isanticipated to be compatible with acetals, amides and silyl ethers. Forfused rings, where the number of substitution sites on the aromatic ringincreases, p may be adjusted appropriately.

A wide variety of substrate aryl groups are useful in the methods of thepresent invention. The choice of substrate will depend on factors suchas the amine, boronic acid, ketone, or the like to be employed and thedesired product, and an appropriate aryl substrate will be made apparentto the skilled artisan by these teachings. It will be understood thatthe aryl substrate preferably will not contain any interferingfunctionalities. It will further be understood that not all activatedaryl substrates will react with every amine, boronic acid, ketone, orthe like.

The reactive the amine, boronic acid, ketone, or the like can be amolecule separate from the substrate aryl group, or a substituent of thesame molecule (e.g., for intramolecular variations).

The amine, boronic acid, ketone, or the like is selected to provide thedesired reaction product. The amine, boronic acid, ketone, or the likemay be functionalized. The amine, boronic acid, ketone, or the like maybe selected from a wide variety of structural types, including but notlimited to, acyclic, cyclic or heterocyclic compounds, fused ringcompounds or phenol derivatives. The aromatic compound and the amine,boronic acid, ketone, or the like may be included as moieties of asingle molecule, whereby the arylation reaction proceeds as anintramolecular reaction.

In certain embodiments, the amine, boronic acid, ketone, or the like isgenerated in situ by conversion of a precursor under the reactionconditions.

In certain embodiments, the aryl substrate and/or the amine, boronicacid, ketone, or the like is attached, either directly or via a tether,to a solid support.

Alternatively, the corresponding salt of the amine, boronic acid,ketone, or the like, may be prepared and used in place of the amine,boronic acid, ketone, or the like. When the corresponding salt of theamine, boronic acid, ketone, or the like is used in the reaction, anadditional base may not be required.

The active form of the transition metal catalyst is not wellcharacterized. Therefore, it is contemplated that the “transition metalcatalyst” of the present invention, as that term is used herein, shallinclude any catalytic transition metal and/or catalyst precursor as itis introduced into the reaction vessel and which is, if necessary,converted in situ into the active form, as well as the active form ofthe catalyst which participates in the reaction.

In preferred embodiments, the transition metal catalyst complex isprovided in the reaction mixture is a catalytic amount. In certainembodiments, that amount is in the range of 0.0001 to 20 mol %, andpreferably 0.05 to 5 mol %, and most preferably 1-3 mol %, with respectto the limiting reagent, which may be either the aromatic compound theamine, boronic acid, ketone, or the like (or the corresponding saltthereof), depending upon which reagent is in stoichiometric excess. Inthe instance where the molecular formula of the catalyst complexincludes more than one metal, the amount of the catalyst complex used inthe reaction may be adjusted accordingly. By way of example, Pd₂(dba)₃has two metal centers; and thus the molar amount of Pd₂(dba)₃ used inthe reaction may be halved without sacrificing catalytic activity.

Catalysts containing palladium and nickel are preferred. It is expectedthat these catalysts will perform similarly because they are known toundergo similar reactions, namely oxidative-addition reactions andreductive-elimination reactions, which are thought to be involved in theformation of the products of the present invention. The novel ligandsare thought to modify the catalyst performance by, for example,modifying reactivity and preventing undesirable side reactions.

As suitable, the catalysts employed in the subject method involve theuse of metals which can mediate cross-coupling of the aryl groups ArXand the amine, boronic acid, ketone, or the like as defined above. Ingeneral, any transition metal (e.g., having d electrons) may be used toform the catalyst, e.g., a metal selected from one of Groups 3-12 of theperiodic table or from the lanthanide series. However, in preferredembodiments, the metal will be selected from the group of latetransition metals, e.g. preferably from Groups 5-12 and even morepreferably Groups 7-11. For example, suitable metals include platinum,palladium, iron, nickel, ruthenium and rhodium. The particular form ofthe metal to be used in the reaction is selected to provide, under thereaction conditions, metal centers which are coordinately unsaturatedand not in their highest oxidation state. The metal core of the catalystshould be a zero valent transition metal, such as Pd or Ni with theability to undergo oxidative addition to Ar—X bond. The zero-valentstate, M(0), may be generated in situ, e.g., from M(II).

To further illustrate, suitable transition metal catalysts includesoluble or insoluble complexes of platinum, palladium and nickel. Nickeland palladium are particularly preferred and palladium is mostpreferred. A zero-valent metal center is presumed to participate in thecatalytic carbon-heteroatom or carbon-carbon bond forming sequence.Thus, the metal center is desirably in the zero-valent state or iscapable of being reduced to metal(0). Suitable soluble palladiumcomplexes include, but are not limited to,tris(dibenzylideneacetone)dipalladium [Pd₂(dba)₃],bis(dibenzylideneacetone)palladium [Pd(dba)₂] and palladium acetate.Alternatively, particularly for nickel catalysts, the active species forthe oxidative-addition step may be in the metal (+1) oxidation state.

Catalysts containing palladium and nickel are preferred. It is expectedthat these catalysts will perform comparably because they are known inthe art to undergo similar reactions, namely cross-coupling reactions,which may be involved in the formation of the products of the presentinvention, e.g., arylamines, diaryls, α-arylketones, or the like.

The coupling can be catalyzed by a palladium catalyst which palladiummay be provided in the form of, for illustrative purposes only, Pd/C,PdCl₂, Pd(OAc)₂, (CH₃CN)₂PdCl₂, Pd[P(C₆H₅)₃]₄, and polymer supportedPd(0). In other embodiments, the reaction can be catalyzed by a nickelcatalyst which nickel may be provided in the form of, for illustrativepurposes only, Ni(acac)₂, NiCl₂[P(C₆H₅)]₂, Ni(1,5-cyclooctadiene)₂,Ni(1,10-phenanthroline)₂, Ni(dppf₂, NiCl₂(dppf),NiCl₂(1,10-phenanthroline), Raney nickel and the like, wherein “acac”represents acetylacetonate.

The catalyst will preferably be provided in the reaction mixture asmetal-ligand complex comprising a bound supporting ligand, that is, ametal-supporting ligand complex. The ligand effects can be key tofavoring, inter alia, the reductive elimination pathway or the likewhich produces the products, rather than side reactions such asβ-hydride elimination. In preferred embodiments, the subject reactionemploys bidentate ligands such as bisphosphines or aminophosphines. Theligand, if chiral can be provided as a racemic mixture or a purifiedstereoisomer. In certain instances, e.g. the improved method for thesynthesis of aryl amines, the use of a racemic, chelating ligand ispreferred.

The ligand, as described in greater detail below, may be a chelatingligand, such as by way of example only, alkyl and aryl derivatives ofphosphines and bisphosphines, amines, diamines, imines, arsines, andhybrids thereof, including hybrids of phosphines with amines. Weakly ornon-nucleophilic stabilizing ions are preferred to avoid undesired sidereactions involving the counter ion. The catalyst complex may includeadditional ligands as required to obtain a stable complex. Moreover, theligand can be added to the reaction mixture in the form of a metalcomplex, or added as a separate reagent relative to the addition of themetal.

The supporting ligand may be added to the reaction solution as aseparate compound or it may be complexed to the metal center to form ametal-supporting ligand complex prior to its introduction into thereaction solution. Supporting ligands are compounds added to thereaction solution which are capable of binding to the catalytic metalcenter. In some preferred embodiments, the supporting ligand is achelating ligand. Although not bound by any theory of operation, it ishypothesized that the supporting ligands suppress unwanted sidereactions as well as enhance the rate and efficiency of the desiredprocesses. Additionally, they typically prevent precipitation of thecatalytic transition metal. Although the present invention does notrequire the formation of a metal-supporting ligand complex, suchcomplexes have been shown to be consistent with the postulate that theyare intermediates in these reactions and it has been observed theselection of the supporting ligand has an affect on the course of thereaction.

The supporting ligand is present in the range of 0.0001 to 40 mol %relative to the limiting reagent, i.e., amine, boronic acid, ketone orthe like, or aromatic compound. The ratio of the supporting ligand tocatalyst complex is typically in the range of about 1 to 20, andpreferably in the range of about 1 to 4 and most preferably 2. Theseratios are based upon a single metal complex and a single binding siteligand. In instances where the ligand contains additional binding sites(i.e., a chelating ligand) or the catalyst contains more than one metal,the ratio is adjusted accordingly. By way of example only, thesupporting ligand BINAP contains two coordinating phosphorus atoms andthus the ratio of BINAP to catalyst is adjusted downward to about 1 to10, preferably about 1 to 2 and most preferably 1. Conversely, Pd₂(dba)₃contains two palladium metal centers and the ratio of a non-chelatingligand to Pd₂(dba)₃ is adjusted upward to 1 to 40, preferably 1 to 8 andmost preferably 4.

In certain embodiments of the subject method, the transition metalcatalyst includes one or more phosphine or aminophosphine ligands, e.g.,as a Lewis basic ligand that controls the stability and electrontransfer properties of the transition metal catalyst, and/or stabilizesthe metal intermediates. Phosphine ligands are commercially available orcan be prepared by methods similar to known processes. The phosphinescan be monodentate phosphine ligands, such as trimethylphosphine,triethylphosphine, tripropylphosphine, triisopropylphosphine,tributylphosphine, tricyclohexylphosphine, trimethyl phosphite, triethylphosphite, tripropyl phosphite, triisopropyl phosphite, tributylphosphite and tricyclohexyl phosphite, in particular triphenylphosphine,tri(o-tolyl)phosphine, triisopropylphosphine or tricyclohexylphosphine;or a bidentate phosphine ligand such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP),1,2-bis(dimethylphosphino)ethane, 1,2-bis(diethylphosphino)ethane,1,2-bis(dipropylphosphino)ethane, 1,2-bis(diisopropylphosphino)ethane,1,2-bis(dibutylphosphino)ethane, 1,2-bis(dicyclohexylphosphino)ethane,1,3-bis(dicyclohexylphosphino)propane,1,3-bis(diisopropylphosphino)propane,1,4-bis(diisopropylphosphino)-butane and2,4-bis(dicyclohexylphosphino)pentane. The aminophosphines may bemonodentate, e.g. each molecule of aminophosphine donates to thecatalytic metal atom only a Lewis basic nitrogen atom or a Lewis basicphosphorus atom. Alternatively, the aminophosphine may be a chelatingligand, e.g. capable of donating to the catalytic metal atom both aLewis basic nitrogen atom and a Lewis basic phosphorus atom.

In some instances, it may be necessary to include additional reagents inthe reaction mixture to promote reactivity of either the transitionmetal catalyst or activated aryl nucleus. In particular, it may beadvantageous to include a suitable base. In general, a variety of basesmay be used in practice of the present invention. It has not beendetermined at which point(s) in the mechanisms of the subjecttransformations the base participates. The base may optionally besterically hindered to discourage metal coordination of the base inthose circumstances where such coordination is possible, i.e., alkalimetal alkoxides. Exemplary bases include such as, by way of exampleonly: alkoxides such as sodium tert-butoxide; alkali metal amides suchas sodium amide, lithium diisopropylamide, and alkali metalbis(trialkylsilyl)amide, e.g., such as lithium bis(trimethylsilyl)amide(LiHMDS) or sodium bis(trimethylsilyl)amide (NaHMDS); tertiary amines(e.g. triethylamine, trimethylamine, 4-(dimethylamino)pyridine (DMAP),1,5-diazabicycl[4.3.0]non-5-ene (DBN),1,5-diazabicyclo[5.4.0]undec-5-ene (DBU); alkali or alkaline earthcarbonate, bicarbonate or hydroxide (e.g. sodium, magnesium, calcium,barium, potassium carbonate, phosphate, hydroxide and bicarbonate). Byway of example only, suitable bases include NaH, LiH, KH, K₂CO₃, Na₂CO₃,Tl₂CO₃, Cs₂CO₃, K(OtBu), Li(OtBu), Na(OtBu) K(OAr), Na(OAr), andtriethylamine, or mixtures thereof. Preferred bases include CsF, K₃PO₄,DBU, NaOt-Bu, KOt-Bu, LiN(i-Pr)₂ (LDA), KN(SiMe₃)₂, NaN(SiMe₃)₂, andLiN(SiMe₃)₂.

Base is used in approximately stoichiometric proportions in the subjectmethods. The present invention has demonstrated that there is no needfor large excesses of base in order to obtain good yields of the desiredproducts under mild reaction conditions. No more than four equivalentsof base, and preferably no more than two equivalents, are needed.Furthermore, in reactions using the corresponding salt of an amine,boronic acid, ketone or the like, additional base may not be required.

As is clear from the above discussion, the products which may beproduced by the amination, Suzuki coupling, and α-arylation reactions ofthis invention can undergo further reaction(s) to afford desiredderivatives thereof. Such permissible derivatization reactions can becarried out in accordance with conventional procedures known in the art.For example, potential derivatization reactions include esterification,oxidation of alcohols to aldehydes and acids, N-alkylation of amides,nitrile reduction, acylation of alcohols by esters, acylation of aminesand the like.

IV. Reaction Conditions

The reactions of the present invention may be performed under a widerange of conditions, though it will be understood that the solvents andtemperature ranges recited herein are not limitative and only correspondto a preferred mode of the process of the invention.

In general, it will be desirable that reactions are run using mildconditions which will not adversely affect the reactants, the catalyst,or the product. For example, the reaction temperature influences thespeed of the reaction, as well as the stability of the reactants andcatalyst. The reactions will usually be run at temperatures in the rangeof 25° C. to 300° C., more preferably in the range 25° C. to 150° C.

In general, the subject reactions are carried out in a liquid reactionmedium. The reactions may be run without addition of solvent.Alternatively, the reactions may be run in an inert solvent, preferablyone in which the reaction ingredients, including the catalyst, aresubstantially soluble. Suitable solvents include ethers such as diethylether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether,tetrahydrofuran and the like; halogenated solvents such as chloroform,dichloromethane, dichloroethane, chlorobenzene, and the like; aliphaticor aromatic hydrocarbon solvents such as benzene, xylene, toluene,hexane, pentane and the like; esters and ketones such as ethyl acetate,acetone, and 2-butanone; polar aprotic solvents such as acetonitrile,dimethylsulfoxide, dimethylformamide and the like; or combinations oftwo or more solvents.

The invention also contemplates reaction in a biphasic mixture ofsolvents, in an emulsion or suspension, or reaction in a lipid vesicleor bilayer. In certain embodiments, it may be preferred to perform thecatalyzed reactions in the solid phase with one of the reactantsanchored to a solid support.

In certain embodiments it is preferable to perform the reactions underan inert atmosphere of a gas such as nitrogen or argon.

The reaction processes of the present invention can be conducted incontinuous, semi-continuous or batch fashion and may involve a liquidrecycle operation as desired. The processes of this invention arepreferably conducted in batch fashion. Likewise, the manner or order ofaddition of the reaction ingredients, catalyst and solvent are also notgenerally critical to the success of the reaction, and may beaccomplished in any conventional fashion. In a order of events that, insome cases, can lead to an enhancement of the reaction rate, the base,e.g. t-BuONa, is the last ingredient to be added to the reactionmixture.

The reaction can be conducted in a single reaction zone or in aplurality of reaction zones, in series or in parallel or it may beconducted batchwise or continuously in an elongated tubular zone orseries of such zones. The materials of construction employed should beinert to the starting materials during the reaction and the fabricationof the equipment should be able to withstand the reaction temperaturesand pressures. Means to introduce and/or adjust the quantity of startingmaterials or ingredients introduced batchwise or continuously into thereaction zone during the course of the reaction can be convenientlyutilized in the processes especially to maintain the desired molar ratioof the starting materials. The reaction steps may be effected by theincremental addition of one of the starting materials to the other.Also, the reaction steps can be combined by the joint addition of thestarting materials to the metal catalyst. When complete conversion isnot desired or not obtainable, the starting materials can be separatedfrom the product and then recycled back into the reaction zone.

The processes may be conducted in either glass lined, stainless steel orsimilar type reaction equipment. The reaction zone may be fitted withone or more internal and/or external heat exchanger(s) in order tocontrol undue temperature fluctuations, or to prevent any possible“runaway” reaction temperatures.

Furthermore, one or more of the reactants can be immobilized orincorporated into a polymer or other insoluble matrix by, for example,derivativation with one or more of substituents of the aryl group.

V. Combinatorial Libraries

The subject reactions readily lend themselves to the creation ofcombinatorial libraries of compounds for the screening ofpharmaceutical, agrochemical or other biological or medically-relatedactivity or material-related qualities. A combinatorial library for thepurposes of the present invention is a mixture of chemically relatedcompounds which may be screened together for a desired property; saidlibraries may be in solution or covalently linked to a solid support.The preparation of many related compounds in a single reaction greatlyreduces and simplifies the number of screening processes which need tobe carried out. Screening for the appropriate biological,pharmaceutical, agrochemical or physical property may be done byconventional methods.

Diversity in a library can be created at a variety of different levels.For instance, the substrate aryl groups used in a combinatorial approachcan be diverse in terms of the core aryl moiety, e.g., a variegation interms of the ring structure, and/or can be varied with respect to theother substituents.

A variety of techniques are available in the art for generatingcombinatorial libraries of small organic molecules. See, for example,Blondelle et al. (1995) Trends Anal. Chem. 14:83; the Affymax U.S. Pat.Nos. 5,359,115 and 5,362,899: the Ellman U.S. Pat. No. 5,288,514: theStill et al. PCT publication WO 94/08051; Chen et al. (1994) JACS116:2661: Kerr et al. (1993) JACS 115:252; PCT publications WO92/10092,WO93/09668 and WO91/07087; and the Lemer et al. PCT publicationWO93/20242). Accordingly, a variety of libraries on the order of about16 to 1,000,000 or more diversomers can be synthesized and screened fora particular activity or property.

In an exemplary embodiment, a library of substituted diversomers can besynthesized using the subject reactions adapted to the techniquesdescribed in the Still et al. PCT publication WO 94/08051, e.g., beinglinked to a polymer bead by a hydrolyzable or photolyzable group, e.g.,located at one of the positions of substrate. According to the Still etal. technique, the library is synthesized on a set of beads, each beadincluding a set of tags identifying the particular diversomer on thatbead. In one embodiment, which is particularly suitable for discoveringenzyme inhibitors, the beads can be dispersed on the surface of apermeable membrane, and the diversomers released from the beads by lysisof the bead linker. The diversomer from each bead will diffuse acrossthe membrane to an assay zone, where it will interact with an enzymeassay. Detailed descriptions of a number of combinatorial methodologiesare provided below.

A) Direct Characterization

A growing trend in the field of combinatorial chemistry is to exploitthe sensitivity of techniques such as mass spectrometry (MS), e.g.,which can be used to characterize sub-femtomolar amounts of a compound,and to directly determine the chemical constitution of a compoundselected from a combinatorial library. For instance, where the libraryis provided on an insoluble support matrix, discrete populations ofcompounds can be first released from the support and characterized byMS. In other embodiments, as part of the MS sample preparationtechnique, such MS techniques as MALDI can be used to release a compoundfrom the matrix, particularly where a labile bond is used originally totether the compound to the matrix. For instance, a bead selected from alibrary can be irradiated in a MALDI step in order to release thediversomer from the matrix, and ionize the diversomer for MS analysis.

B) Multipin Synthesis

The libraries of the subject method can take the multipin libraryformat. Briefly, Geysen and co-workers (Geysen et al. (1984) PNAS81:3998-4002) introduced a method for generating compound libraries by aparallel synthesis on polyacrylic acid-grated polyethylene pins arrayedin the microtitre plate format. The Geysen technique can be used tosynthesize and screen thousands of compounds per week using the multipinmethod, and the tethered compounds may be reused in many assays.Appropriate linker moieties can also been appended to the pins so thatthe compounds may be cleaved from the supports after synthesis forassessment of purity and further evaluation (c.f., Bray et al. (1990)Tetrahedron Lett 31:5811-5814; Valerio et al. (1991) Anal Biochem197:168-177; Bray et al. (1991) Tetrahedron Lett 32:6163-6166).

C) Divide-Couple-Recombine

In yet another embodiment, a variegated library of compounds can beprovided on a set of beads utilizing the strategy ofdivide-couple-recombine (see, e.g., Houghten (1985) PNAS 82:5131-5135;and U.S. Pat. Nos. 4,631,211; 5,440,016; 5,480,971). Briefly, as thename implies, at each synthesis step where degeneracy is introduced intothe library, the beads are divided into separate groups equal to thenumber of different substituents to be added at a particular position inthe library, the different substituents coupled in separate reactions,and the beads recombined into one pool for the next iteration.

In one embodiment, the divide-couple-recombine strategy can be carriedout using an analogous approach to the so-called “tea bag” method firstdeveloped by Houghten, where compound synthesis occurs on resin sealedinside porous polypropylene bags (Houghten et al. (1986) PNAS82:5131-5135). Substituents are coupled to the compound-bearing resinsby placing the bags in appropriate reaction solutions, while all commonsteps such as resin washing and deprotection are performedsimultaneously in one reaction vessel. At the end of the synthesis, eachbag contains a single compound.

D) Combinatorial Libraries by Light-Directed, Spatially AddressableParallel Chemical Synthesis

A scheme of combinatorial synthesis in which the identity of a compoundis given by its locations on a synthesis substrate is termed aspatially-addressable synthesis. In one embodiment, the combinatorialprocess is carried out by controlling the addition of a chemical reagentto specific locations on a solid support (Dower et al. (1991) Annu RepMed Chem 26:271-280; Fodor, S. P. A. (1991) Science 251:767; Pirrung etal. (1992) U.S. Pat. No. 5,143,854; Jacobs et al. (1994) TrendsBiotechnol 12:19-26). The spatial resolution of photolithography affordsminiaturization. This technique can be carried out through the useprotection/deprotection reactions with photolabile protecting groups.

The key points of this technology are illustrated in Gallop et al.(1994) J Med Chem 37:1233-1251. A synthesis substrate is prepared forcoupling through the covalent attachment of photolabilenitroveratryloxycarbonyl (NVOC) protected amino linkers or otherphotolabile linkers. Light is used to selectively activate a specifiedregion of the synthesis support for coupling. Removal of the photolabileprotecting groups by light (deprotection) results in activation ofselected areas. After activation, the first of a set of amino acidanalogs, each bearing a photolabile protecting group on the aminoterminus, is exposed to the entire surface. Coupling only occurs inregions that were addressed by light in the preceding step. The reactionis stopped, the plates washed, and the substrate is again illuminatedthrough a second mask, activating a different region for reaction with asecond protected building block. The pattern of masks and the sequenceof reactants define the products and their locations. Since this processutilizes photolithography techniques, the number of compounds that canbe synthesized is limited only by the number of synthesis sites that canbe addressed with appropriate resolution. The position of each compoundis precisely known; hence, its interactions with other molecules can bedirectly assessed.

In a light-directed chemical synthesis, the products depend on thepattern of illumination and on the order of addition of reactants. Byvarying the lithographic patterns, many different sets of test compoundscan be synthesized simultaneously; this characteristic leads to thegeneration of many different masking strategies.

E) Encoded Combinatorial Libraries

In yet another embodiment, the subject method utilizes a compoundlibrary provided with an encoded tagging system. A recent improvement inthe identification of active compounds from combinatorial librariesemploys chemical indexing systems using tags that uniquely encode thereaction steps a given bead has undergone and, by inference, thestructure it carries. Conceptually, this approach mimics phage displaylibraries, where activity derives from expressed peptides, but thestructures of the active peptides are deduced from the correspondinggenomic DNA sequence. The first encoding of synthetic combinatoriallibraries employed DNA as the code. A variety of other forms of encodinghave been reported, including encoding with sequenceable bio-oligomers(e.g., oligonucleotides and peptides), and binary encoding withadditional non-sequenceable tags.

1) Tagging With Sequenceable Bio-Oligomers

The principle of using oligonucleotides to encode combinatorialsynthetic libraries was described in 1992 (Brenner et al. (1992) PNAS89:5381-5383), and an example of such a library appeared the followingyear (Needles et al. (1993) PNAS 90:10700-10704). A combinatoriallibrary of nominally 7⁷ (=823,543) peptides composed of all combinationsof Arg, Gln, Phe, Lys, Val, D-Val and Thr (three-letter amino acidcode), each of which was encoded by a specific dinucleotide (TA, TC, CT,AT, TT, CA and AC, respectively), was prepared by a series ofalternating rounds of peptide and oligonucleotide synthesis on solidsupport. In this work, the amine linking functionality on the bead wasspecifically differentiated toward peptide or oligonucleotide synthesisby simultaneously preincubating the beads with reagents that generateprotected OH groups for oligonucleotide synthesis and protected NH₂groups for peptide synthesis (here, in a ratio of 1:20). When complete,the tags each consisted of 69-mers, 14 units of which carried the code.The bead-bound library was incubated with a fluorescently labeledantibody, and beads containing bound antibody that fluoresced stronglywere harvested by fluorescence-activated cell sorting (FACS). The DNAtags were amplified by PCR and sequenced, and the predicted peptideswere synthesized. Following such techniques, compound libraries can bederived for use in the subject method, where the oligonucleotidesequence of the tag identifies the sequential combinatorial reactionsthat a particular bead underwent, and therefore provides the identity ofthe compound on the bead.

The use of oligonucleotide tags permits exquisitely sensitive taganalysis. Even so, the method requires careful choice of orthogonal setsof protecting groups required for alternating co-synthesis of the tagand the library member. Furthermore, the chemical lability of the tag,particularly the phosphate and sugar anomeric linkages, may limit thechoice of reagents and conditions that can be employed for the synthesisof non-oligomeric libraries. In preferred embodiments, the librariesemploy linkers permitting selective detachment of the test compoundlibrary member for assay.

Peptides have also been employed as tagging molecules for combinatoriallibraries. Two exemplary approaches are described in the art, both ofwhich employ branched linkers to solid phase upon which coding andligand strands are alternately elaborated. In the first approach (Kerr JM et al. (1993) J Am Chem Soc 115:2529-2531), orthogonality in synthesisis achieved by employing acid-labile protection for the coding strandand base-labile protection for the compound strand.

In an alternative approach (Nikolaiev et al. (1993) Pept Res 6:161-170),branched linkers are employed so that the coding unit and the testcompound can both be attached to the same functional group on the resin.In one embodiment, a cleavable linker can be placed between the branchpoint and the bead so that cleavage releases a molecule containing bothcode and the compound (Ptek et al. (1991) Tetrahedron Lett32:3891-3894). In another embodiment, the cleavable linker can be placedso that the test compound can be selectively separated from the bead,leaving the code behind. This last construct is particularly valuablebecause it permits screening of the test compound without potentialinterference of the coding groups. Examples in the art of independentcleavage and sequencing of peptide library members and theircorresponding tags has confirmed that the tags can accurately predictthe peptide structure.

2) Non-Sequenceable Tagging: Binary Encoding

An alternative form of encoding the test compound library employs a setof non-sequencable electrophoric tagging molecules that are used as abinary code (Ohlmeyer et al. (1993) PNAS 90:10922-10926). Exemplary tagsare haloaromatic alkyl ethers that are detectable as theirtrimethylsilyl ethers at less than femtomolar levels by electron capturegas chromatography (ECGC). Variations in the length of the alkyl chain,as well as the nature and position of the aromatic halide substituents,permit the synthesis of at least 40 such tags, which in principle canencode 2⁴⁰ (e.g., upwards of 10¹²) different molecules. In the originalreport (Ohlmeyer et al., supra) the tags were bound to about 1% of theavailable amine groups of a peptide library via a photocleavableo-nitrobenzyl linker. This approach is convenient when preparingcombinatorial libraries of peptide-like or other amine-containingmolecules. A more versatile system has, however, been developed thatpermits encoding of essentially any combinatorial library. Here, thecompound would be attached to the solid support via the photocleavablelinker and the tag is attached through a catechol ether linker viacarbene insertion into the bead matrix (Nestler et al. (1994) J Org Chem59:4723-4724). This orthogonal attachment strategy permits the selectivedetachment of library members for assay in solution and subsequentdecoding by ECGC after oxidative detachment of the tag sets.

Although several amide-linked libraries in the art employ binaryencoding with the electrophoric tags attached to amine groups, attachingthese tags directly to the bead matrix provides far greater versatilityin the structures that can be prepared in encoded combinatoriallibraries. Attached in this way, the tags and their linker are nearly asunreactive as the bead matrix itself. Two binary-encoded combinatoriallibraries have been reported where the electrophoric tags are attacheddirectly to the solid phase (Ohlmeyer et al. (1995) PNAS 92:6027-6031)and provide guidance for generating the subject compound library. Bothlibraries were constructed using an orthogonal attachment strategy inwhich the library member was linked to the solid support by aphotolabile linker and the tags were attached through a linker cleavableonly by vigorous oxidation. Because the library members can berepetitively partially photoeluted from the solid support, librarymembers can be utilized in multiple assays. Successive photoelution alsopermits a very high throughput iterative screening strategy: first,multiple beads are placed in 96-well microtiter plates; second,compounds are partially detached and transferred to assay plates; third,a metal binding assay identifies the active wells; fourth, thecorresponding beads are rearrayed singly into new microtiter plates;fifth, single active compounds are identified; and sixth, the structuresare decoded.

EXEMPLIFICATION

The invention may be understood with reference to the followingexamples, which are presented for illustrative purposes only and whichare non-limiting. The substrates utilized in these examples were eithercommercially available, or were prepared from commercially availablereagents.

Example 1

A Highly Active Catalyst for Palladium-Catalyzed Cross-CouplingReactions: Room Temperature Suzuki Couplings and Amination ofUnactivated Aryl Chlorides

A highly active palladium catalyst which employs the chelatingaminophosphine ligand1-(N,N-dimethylamino)-1′-(dicyclohexylphosphino)biphenyl (2) has beendeveloped. This catalyst is effective for the cross-coupling of arylchlorides with amines, boronic acids, and ketone enolates. The system issufficiently reactive to allow for the room temperature amination ofaryl bromides and electron-deficient aryl chlorides, and promotes roomtemperature Suzuki coupling reactions of both electron-rich andelectron-deficient aryl chlorides. The coordination of the amine moietymay be key to the enhanced reactivity and catalyst stability of thissystem.

Palladium-catalyzed C—N bond-forming reactions have evolved into aversatile and efficient synthetic transformation. The use of palladiumcatalysts supported by bidentate phosphine ligands has made possiblesubstitution of aryl halides and triflates with nitrogen,¹ oxygen,² andcertain carbon nucleophiles.³ The lack of a general palladium-basedcatalyst for aryl chloride substitution reactions,^(4,5) as well as theelevated reaction temperatures often required prompted us to search fornew ligands which might overcome these limitations.

¹H NMR studies in our laboratories of the amination reactions of arylbromides catalyzed by BINAP/Pd(OAc)₂ suggested that oxidative additionwas rate limiting.⁶ For aryl chlorides, oxidative addition can beanticipated to be even more sluggish. To facilitate this slow step, webegan to explore the use of electron-rich phosphine ligands.^(4, 5d, 7a)An initial experiment which employed PCy₃ as the palladium-supportingligand demonstrated that although this type of catalyst was capable ofactivating the carbon-chlorine bond, the process suffered from facileβ-hydride elimination and subsequent formation of reduced arene.^(5a)Based on our knowledge that bidentate ligands suppressed β-hydrideelimination in arylations of primary amines,^(1c) we focused our effortson the preparation of electron-rich bidentate phosphines.⁶ We firstprepared the known 1,1′-bis(dicyclohexylphosphino)binaphthyl (1).⁸Initial screening demonstrated that 1/Pd(0) constituted a reasonablyeffective catalyst for the coupling of pyrrolidine with chlorotoluene.This important result, taken together with our experience with bidentatemonophosphines PPF-OMe and PPFA^(1d) prompted us to prepareaminophosphine ligand 2.⁹ In comparison to 1, use of ligand 2 isgenerally superior and significantly expands the scope ofpalladium-catalyzed aryl chloride transformations. Herein, wedemonstrate that the 2/Pd(0) catalyst system is highly active and allowsfor the room temperature amination of aryl bromides and the firstexample of a room temperature amination of an aryl chloride. Moreover,this system functions as the first general catalyst for room temperatureSuzuki coupling reactions of aryl chlorides.

To demonstrate the efficacy of the 2/Pd(0) catalyst system, we haveprepared several aniline derivatives from aryl chlorides (Table 1,entries 1-2,4-6,8-9, 13, 16). Secondary amines give excellent results inthe coupling procedure (Table 1, entries 1-2,4-6, 8-9), and thearylation of a primary aniline can also be accomplished (Table 1, entry16). Primary alkyl amines are efficient coupling partners provided thearyl chloride is substituted at the ortho position (Table 1, entry 13),or through the use of ligand 1 (Table 1, entries 14,17). Catalyst levelsas low as 0.05 mol % Pd have been achieved in the reaction ofchlorotoluene with di-n-butylamine (Table 1, entry 1).

Given the high reactivity of this catalyst, we explored the possibilityof carrying out room temperature aminations. We found that both aryliodides and aryl bromides (Table 1, entries 3, 7, 10, 15) reactedreadily at room temperature when DME was employed as the solvent. Theexperimentally simple procedure did not require crown ether or otheradditives.^(1e) Broadly speaking, the room temperature amination of arylbromides displays the same scope as the reactions of aryl chlorides at80° C. Aryl bromides containing functional groups sensitive to NaOt-Bucould be converted to the corresponding aniline derivative by usingK₃PO₄ as the base. In these reactions (Table 1, entries 11 and 12),heating at 80° C. was required due to the decreased basicity and/orsolubility of K₃PO₄.

Using 2/Pd(0) the first amination of an aryl chloride (albeit anactivated one) at room temperature could also be achieved for the firsttime.¹⁰ Thus, the coupling of p-chlorobenzonitrile and morpholine wascatalyzed by 2.5 mol % Pd₂(dba)₃, 7.5 mol % 2 and NaOt-Bu in DME at roomtemperature to provide the corresponding aniline derivative in 96% yield(Table 1, entry 9).

TABLE 1 Catalytic Amination^(a) of Aryl Chlorides and Br mid s

^((a))Reaction Conditions: 1.0 equiv. aryl halide, 1.2 equiv. amine, 1.4equiv. NaOtBu, 0.5 mol % Pd₂(dba)₃, 1.5 mol % ligand (1.5 L/Pd), toluene(2 mL/mmol halide), 80° C. Reactions were complete in 11–27 h; reactiontimes have not been minimized. ^((b))Reaction run at room temperature inDME solvent. ^((c))Reaction run with 1.5 mol % Pd₂(dba)₃. ^((d))Reactionrun with 2.5 mol % Pd₂(dba)₃. ^((e))Reaction run using K₃PO₄, DMEsolvent. ^((f))Reaction run using Pd(OAc)₂, K₃PO₄, DME solvent.^((g))One of two runs only proceeded to 98% conversion. ^((h))Reactionrun at 100° C. ^((i))Reaction run with Pd(OAc)₂, ligand 1, Cs₂CO₃ ascatalyst, ligand, and base. ^((j))Using 1 as ligand. ^((k))[ArBr] = 1M.^((l))[ArBr] = 2M. ^((m))1.5 equiv. benzylamine used.

In light of the high reactivity of this new catalyst system in aminationreactions, we proceeded to examine its utility in several differentPd-catalyzed C—C bond forming reactions. Pd-catalyzed Suzuki couplingreactions¹¹ which use aryl chlorides as substrates generally requirefairly high reaction temperatures (>90° C.), and are usually inefficientif the aryl halide does not contain electron-withdrawing substituents.⁷While nickel catalysts are more efficient at promoting Suzuki couplingreactions of electronically-neutral or electron-rich aryl chlorides,sterically hindered substrates are often problematic due to the smallsize of nickel relative to palladium.¹² Furthermore, examples of Suzukicoupling reactions which proceed at room temperature are rare,¹³ andoften require stoichiometric amounts of highly toxic thalliumhydroxide.^(13b,c,d) To the best of our knowledge, no examples of roomtemperature Suzuki couplings of an aryl chloride have been reported.

We have found that Suzuki coupling reactions of both aryl bromides andaryl chlorides proceed in high yield at room temperature using the2/Pd(0) catalyst system and CsF¹⁴ in dioxane solvent (Table 2, entries2,5,7-10).^(15,16) These conditions allow for the coupling of bothelectron-rich and electron-deficient aryl chlorides, and tolerate thepresence of base-sensitive functional groups. An aryl-alkyl couplingreaction of an aryl chloride using an alkylboron reagent generated insitu from 1-hexene and 9-BBN¹⁷ was achieved at 50° C.; the highertemperature presumably being necessary due to the increased size of theboron reagent and the slower rate of transmetallation of alkyl groupsrelative to aryl groups.¹⁷ Suzuki coupling reactions of electron-richaryl chlorides could also be carried out using inexpensive K₃PO₄ withonly 0.5 mol % palladium catalyst, although temperatures of 100° C. wererequired.

We also found the 2/Pd(0) catalyst system was effective for thePd-catalyzed α-arylation of ketones.³ Coupling of 5-bromo-m-xylene with2-methyl-3-pentanone was performed at room temperature using NaHMDS asbase (Table 2, entry 12). Interestingly, while the BINAP catalyst systemwas selective at promoting the monoarylation of methyl ketones, 2/Pd wasselective for the diarylation of methyl ketones (Table 2, entry 11).This may be due to the decreased steric bulk of the dimethylamineportion of 2 relative to the diphenylphosphine group of BINAP.

Other Pd-catalyzed cross couplings of aryl chlorides were surveyed usingthis catalyst. Stille couplings,¹⁸ Sonogashira couplings,¹⁹ andcross-couplings of aryl halides with organozinc reagents gave nodetectable products.²⁰ The Heck arylation²¹ of styrene gave someconversion to product at 110° C.

TABLE 2 Suzuki Coupling^(a) and K ton Arylation mol % Entry HalideCoupling Partner Temp Pd Yield Product  1 2

PhB(OH)₂ 100rt 0.52.0 96^(b)94

3 o-MeOPhB(OH)₂ 100 1.0 94^(d)

 4 5

PhB(OH)₂ 100rt 0.52.0 93^(b)92

 6

 50 2.0 88^(c)

 7

PhB(OH)₂ rt 1.0 92

 8

m-TolB(OH)₂ rt 2.0 94

 9

PhB(OH)₂ rt 2.0 90

10

m-TolB(OH)₂ rt 2.0 92

11

 80 3.0 79^(d)

12

rt 3.0 82^(e)

^((a))Reaction Conditions: 1.0 equiv. aryl halide, 1.5 equiv. boronreagent, 3.0 equiv. CsF, 0.5–2.0 mol % Pd(OAc)₂, 0.75–3.0 mol % 2 (1.5L/Pd), dioxane (3 mL/mmol halide). Reactions were complete in 19–30 h;reaction times have not been minimized. ^((b))2.0 equiv. K₃PO₄ used inplace of CsF. ^((c))One of two runs only proceeded to 98% conversion.^((d))Pd₂(dba)₃, NaOtBu used as catalyst, base. ^((e))Pd₂(dba)₃, NaHMDSused as catalyst, base

While the precise mechanistic details of the reactions promoted by the2/Pd(0) catalyst system remain unknown, we believe that the overallcatalytic cycle for the amination reaction is similar to that postulatedfor the BINAP/Pd catalyzed amination of aryl bromides.^(1c) However, inreactions catalyzed by 2/Pd there may be different pathways availablefor the amine coordination/deprotonation step. Our current view is apathway which involves binding of the amine to four-coordinate complexI, followed by deprotonation of the resulting five-coordinate complex IIto give III (Scheme 1, path A). Alternatively, coordination of the aminesubstrate may occur after initial dissociation of the dimethylaminomoiety of the ligand, followed by nucleophilic attack of the aminesubstrate on three-coordinate^(22b) complex IV to give V. Deprotonationof V is followed by rapid recomplexation of the ligand amine group togive III (Scheme 1, path B).²² If path B is operative, therecomplexation of the amine is presumably fast relative to β-hydrideelimination since little or no reduced side product is observed. Thisnotion is supported by the fact that Cy₂PPh was not an effective ligandfor any of these Pd-catalyzed processes;^(15,16) amination reactionsconducted with electron-rich monodentate phosphines as ligands such asCy₃P or Cy₂PPh demonstrated that reduction via β-hydride elimination canbe a significant problem without a chelating group on the ligand. Therelatively small size of the amine group in 2 allows for the efficientcoupling of both cyclic and acyclic secondary amines.^(1d) That 2/Pd(0)can be employed in an amination procedure at the 0.05 mol % level (Table1, entry 1) suggests that the dimethylamino group also contributes tothe stability of the catalyst.

The failure of the 2/Pd(0) catalyst system to promote the Heck, Stille,Sonogashira, and zinc cross-coupling reactions suggests the C—C bondforming reactions discussed in this paper proceed throughfour-coordinate intermediates with both the amine and phosphine moietiesbound to the metal during the key steps in the catalytic cycle. If theligand is bound in a bidentate fashion, transmetallation from Sn, Cu orZn, or olefin coordination would be slow.^(21,23) This argument issupported by the fact that Suzuki couplings and ketone arylationreactions are generally efficient with chelating phosphine ligands,while Stille reactions are not. Although in some cases Heck reactionsare efficient with chelating ligands, these are usually with cationiccomplexes or for intramolecular reactions.²¹

We hope that modification of the design of this ligand or furtheroptimization of reaction conditions may lead to efficient Heckolefinations of electron-rich aryl chlorides.²⁴ Further studies towardsdevelopment of highly active catalysts for these and other processes arecurrently underway.

REFERENCES AND NOTES FOR EXAMPLE 1

-   (1) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.    Int. Ed. Engl. 1995, 34, 1348-1349; (b) Wolfe, J. P.; Rennels, R.    A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525-7546. (c) Wolfe, J.    P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,    7215-7216; (d) Marcoux, J.-F.; Wagaw, S.; Buchwald, S. L. J. Org.    Chem. 1997, 62, 1568-1569; (e) Wolfe, J. P.; Buchwald, S. L. J. Org.    Chem. 1997, 62, 6066-6068. (f) Wolfe, J. P.; Wagaw, S.; Marcoux,    J.-F.; Buchwald, S. L. Acc. Chem. Res. Submitted for    publication; (g) Louie, J.; Hartwig, J. Tetrahedron Lett. 1995, 36,    3609-3612; (h) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996,    118, 7217-7218; (i) Barañano, D.; Mann, G.; Hartwig, J. F. Cur. Org.    Chem. 1997, 1, 287-305. (j) Hartwig, J. F. Synlett 1997, 329-340.-   (2) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.    1996, 118, 10333-10334; (b) Palucki, M.; Wolfe, J. P.;    Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 3395-3396; (d) Mann,    G.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 13109-13110; (e)    Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413-5418.-   (3) (a) Palucki, M.; Buchwald. S. L. J. Am. Chem. Soc. 1997, 119,    11108-11109; (b) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki,    M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918; (c)    Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119,    12382-12383; (d) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.    Angew. Chem. Int. Ed. Engl. 1997, 46, 1740-1742.-   (4) Aryl chlorides are attractive starting materials from the    perspective of cost and availability, but are less reactive than    aryl bromides and iodides. See: Grushin, V. V.; Alper, H. Chem. Rev.    1994, 94, 1047-1062.-   (5) Existing protocols for the amination of aryl chlorides include    our work in nickel catalysis as well as two palladium-based methods.    Our nickel-based work, while quite effective for a wide variety of    aryl chloride substrates, is not effective for amination of other    aryl halides and does not tolerate base-sensitive functional groups.    The palladium methods are quite limited in scope and often result in    mixtures of products. See: (a) Wolfe, J. P.; Buchwald, S. L; J. Am.    Chem. Soc. 1997, 119, 6054-6058; (b) Beller, M.; Riermeier, T. H.;    Reisinger, C.-P.; Herrmann, W. A. Tetrahedon Lett. 1997, 38,    2073-2074; (c) Riermeier, T. H.; Zapf, A.; Beller, M. Top. Catal.    1997, 4, 301-309; (d) Reddy, N. P.; Tanaka, M. Tetrahedon Lett.    1997, 38, 4807-4810. (e) Nishiyama, M.; Yamamoto, T.; Koie, Y.    Tetrahedron Lett. 1998, 39, 617-620; (f) Yamamoto, T.; Nishiyama,    M.; Koie, Y. Tetrahedron Lett. 1998, 39, 2367-2370.-   (6) Hartwig and Hamann have recently reported similar NMR    experiments. They have also shown that electron-rich bidentate    bis-phosphines can be used for the Pd-catalyzed amination of aryl    chlorides: Hartwig, J. F.; Hamann, B. C. Submitted for Publication.-   (7) (a) Shen, W. Tetrahedron Lett. 1997, 38, 5575-5578. (b) Beller,    M.; Fischer, H.; Herrmann, W. A.; Öfele, K.; Brossmer, C. Angew.    Chem. Int. Ed. Engl. 1995, 34, 1848-1849.-   (8) Zhang, X.; Mashima, K.; Koyano, K.; Sayo, N.; Kumobayashi, H.;    Akutagawa, S.; Takaya, H. J. Chem. Soc. Perkin Trans. 11994,    2309-2322.-   (9) Ligand 2 was prepared in 3 steps from    N,N-dimethyl-2-bromoaniline. The ligand is obtained as a crystalline    solid and is stored and handled in the air without any special    precautions. Under these conditions, the ligand is stable for at    least a month without any detectable oxidation. See supporting    information for complete experimental details.-   (10) Control experiments conducted in the absence of palladium    afforded no coupled products after 24 h at room temperature.-   (11) Suzuki, A. in Metal-Catalyzed Cross-Coupling Reactions    Diederich, F.; Stang, P. J. Eds., Wiley-VCH, Weinheim, Germany,    1998, Ch. 2. (c) Bumagin, N. A.; Bykov. V. V. Tetrahedron 1997, 53,    14437-14450. (d) Mitchell, M. B.; Wallbank, P. J. Tetrahedron Lett.    1991, 32, 2273-2276. (e) Firooznia, F.; Gude, C.; Chan, K.;    Satoh, Y. Tetrahedron Lett. 1998, 39, 3985-3988. (f) Cornils, B.    Orgn. Proc. Res. Dev. 1998, 2, 121-127.-   (12) (a) Indolese, A. F. Tetrahedron Lett. 1997, 38, 3513-3516. (b)    Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997, 62,    8024-8030.-   (13) (a) Campi, E. M.; Jackson, W. R.; Marcuccio, S. M.;    Naeslund, C. G. M J. Chem. Soc., Chem. Commun. 1994, 2395. (b)    Anderson, J. C.; Namli, H.; Roberts, C. A. Tetrahedron 1997, 53,    15123-15134. (c) Anderson, J. C.; Namli, H. Synlett 1995,    765-766. (d) Uenishi, J.-i.; Beau, J.-M.; Armstrong, R. W.;    Kishi, Y. J. Am. Chem. Soc. 1987, 109, 4756-4758.-   (14) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.    1994, 59, 6095-6097.-   (15) See supporting information for complete experimental details.-   (16) Control experiments conducted using dicyclohexylphenylphosphine    in place of 2 gave low conversions and low yields of products.¹⁵-   (17) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;    Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314-321.-   (18) Stille, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508.-   (19) Sonogashira, K. in ref 11, Ch 5.-   (20) Knochel, P. in ref 11, Ch 9.-   (21) (a) de Meijere, A.; Meyer, F. E. Angew. Chem. Int. Ed. Engl.    1994, 33, 2379-2411; (b) Bräse, S.; de Meijere, A. in ref. 11, Ch.    3.-   (22) (a) It is also possible that reductive elimination occurs from    a 3-coordinate intermediately formed by deprotonation of V. (b)    There is precedent for the dissociation of one phosphine of a    chelating bis-phosphine.^(1j) (c) In reactions which employ NaOt-Bu    as base it is possible that complexes shown in FIG. 1 may contain    X=OtBu.^(2d) In reactions which employ Cs₂CO₃ or K₃PO₄ as base it is    unlikely that carbonate or phosphate complexes form due to the low    solubility and low nucleophilicity of Cs₂CO₃ and K₃PO₄ relative to    NaOt-Bu.-   (23) Farina, V. Pure Appl. Chem. 1996, 68, 73-78.-   (24) Heck reactions of aryl chlorides generally require high    reaction temperatures, and are often inefficient for electron-rich    aryl chlorides. See ref 5a and references therein. (a) Herrmann, W.    A.; Brossmer, C.; Reisinger, C. -P.; Riermeier, T. H.; Öfele, K.;    Beller, M. Chem. Eur. J. 1997, 3, 1357-1364. (b) Reetz, M. T.;    Lohmer, G.; Schwickardi, R. Angew. Chem. Int. Ed. Engl. 1998, 37,    481-483. (c) Ohff, M.; Ohff, A.; van der Boom, M. E.;    Milstein, D. J. Am. Chem. Soc. 1997, 119, 11687-11688.    Supporting Information for Example 1

General. All reactions were carried out under an argon atmosphere inoven-dried glassware. Elemental analyses were performed by E & RMicroanalytical Laboratory Inc., Parsippany, N.J. Toluene was distilledunder nitrogen from molten sodium. THF was distilled under argon fromsodium benzophenone ketyl. Unless stated otherwise, commerciallyobtained materials were used without purification. Aryl halides werepurchased from Aldrich Chemical company except for 4-chloroacetophenonewhich was purchased from Fluka Chemical company.N,N-dimethyl-2-bromoaniline¹ was prepared by alkylation of2-bromoaniline with iodomethane in DMF in the presence of sodiumcarbonate. Tribasic potassium phosphate was purchased from FlukaChemical company. Cesium fluoride was purchased from Strem Chemicalcompany and was ground with a mortar and pestle before use. Cesiumcarbonate was obtained from Chemetal and was ground with a mortar andpestle before use. Phenylboronic acid, chlorodicyclohexylphosphine,palladium acetate, tris(dibenzylideneacetone)dipalladium(0),(±)-2,2′-dibromo-1,1′-binaphthyl, and n-butyllithium were purchased fromStrem Chemical company. 2-Methoxyphenylboronic acid² and3-methylphenylboronic acid² were prepared by lithiation of thecorresponding halide and reaction with B(OMe)₃ according to a generalliterature procedure.² These boronic acids were obtained in ˜85-95%purity following crystallization from pentane/ether and were usedwithout further purification. Trimethyl borate, triisopropyl borate,9-BBN (0.5 M THF solution), NaHMDS (95%), 2-methyl-3-pentanone,3-methyl-2-butanone, anhydrous dioxane, anhydrous DME,dicyclohexylphenylphosphine, and 1-hexene were purchased from AldrichChemical company. (±)-2,2′-Bis(dicyclohexylphosphino)-1,1′-binaphthyl 1³was prepared by metallation of the corresponding dibromobinaphthyl witht-butyllithium and quenching with chlorodicyclohexylphosphine using aprocedure analogous to the synthesis of (±)-BINAP.⁴ It was characterizedby elemental analysis and by comparison of its ¹H and ³¹P NMR spectrawith literature data.³ Tetrakis(triphenylphosphine)palladium wasprepared according to a literature procedure.⁵ Sodium t-butoxide waspurchased from Aldrich Chemical Company; the bulk of this material wasstored under nitrogen in a Vacuum Atmospheres glovebox. Small portions(1-2 g) were removed from the glovebox in glass vials, stored in the airin desiccators filled with anhydrous calcium sulfate, and weighed in theair. IR spectra reported in this paper were obtained by placing neatsamples directly on the DiComp probe of an ASI REACTIR in situ IRinstrument. Yields in Tables 1 and 2 refer to isolated yields (averageof two runs) of compounds estimated to be=95% pure as determined by ¹HNMR, and GC analysis or combustion analysis. Entries 1,⁶ 2,⁷ 3,⁶ 4,⁶ 5,⁸6,⁹ 7,⁶ 8,⁶ 9,¹¹ 13,⁶ and 14,¹⁰ from Table 1 have been previouslyreported by this group and were characterized by comparison of their ¹HNMR spectra to those of samples prepared prior to this work; theirpurity was confirmed by GC analysis. The procedures described in thissection are representative, thus the yields may differ from those givenin Tables 1 and 2.

2-(N,N-Dimethylamino)-2′-(dicyclohexylphosphino)biphenyl (2).

N,N-dimethylamino-2-bromoaniline¹ (4.0 g, 20.0 mmol) was loaded into anoven-dried flask which had been cooled to room temperature under anargon purge. The flask was purged with argon and THF (20 mL) was added.The solution was cooled to −78° C. and n-butyllithium (13.1 mL, 21.0mmol, 1.6 M in hexanes) was added dropwise with stirring. After theaddition was complete the reaction mixture was stirred at −78° C. for 75min during which time a white precipitate formed. An additional 70 mL ofTHF was added, and the aryllithium suspension was then transferred viacannula to a separate flask containing a solution of triisopropyl borate(9.2 mL, 40.0 mmol) in THF (20 mL) which had been cooled to −78° C. Thereaction mixture was stirred at −78° C. for 1 h, then warmed to roomtemperature and allowed to stir overnight (25 h). The reaction wasquenched with 1 M aqueous HCl (250 mL), and stirred at room temperaturefor 15 min. The pH of the mixture was adjusted to pH 7 with 6 M aqueousNaOH, and the mixture was transferred to a separatory funnel. Themixture was extracted with ether (3×150 mL), and the combined organicextracts were dried over anhydrous magnesium sulfate, and concentratedin vacuo to give a brown oil which contained substantial amounts ofN,N-dimethylaniline. This oil was then taken up in ether (100 mL), andextracted with 1 M aqueous NaOH (3×100 mL). The organic layer wasdiscarded and the aqueous extracts were adjusted to pH 7 with 6 Maqueous HCl. The aqueous phase was then extracted with ether (3×100 mL),and the combined organic layers were dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to give 1.85 g of2-(N,N-dimethylamino)phenylboronic acid¹² as a viscous tan oil which wasfound to be ˜50-60% pure by ¹H NMR. This material was used withoutfurther purification.

The crude boronic acid was taken up in ethanol (5 mL) and was added to aflask containing a solution of tetrakis(triphenylphosphine)palladium⁵(700 mg, 0.61 mmol, 5 mol %) and 2-bromoiodobenzene (4.1 g, 14.5 mmol)in DME (100 mL) under argon. A solution of Na₂CO₃ (6.42 g, 60.6 mmol) indegassed water (30 mL) was added to the reaction vessel, and the mixturewas heated to reflux for 48 h. The reaction mixture was then cooled toroom temperature, diluted with ether (200 mL), and poured into aseparatory funnel. The layers were separated, and the aqueous layer wasextracted with ether (200 mL). The layers were separated and the aqueouslayer was discarded. The combined organic layers were then washed with 1M aqueous NaOH (50 mL), and the aqueous wash was discarded. The combinedorganic fractions were then extracted with 1 M aqueous HCl (4×150 mL).The organic fraction was discarded, and the combined aqueous acidextracts were basified to pH 14 with 6 M aqueous NaOH. The aqueous phasewas extracted with ether (3×150 mL), and the combined organic layerswere dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo to give 2.1 g of a white solid which was judged to be 90-95%pure by ¹H NMR. This material was used without further purification.

An oven-dried round-bottomed flask was cooled to room temperature underan argon purge and charged with the crude1-(N,N-dimethylamino)-1′-bromobiphenyl. The flask was purged with argon,and THF (120 mL) was added. The solution was cooled to −78° C. withstirring, and n-butyllithium (5.2 mL, 8.37 mmol, 1.6 M in hexanes) wasadded dropwise. The solution was stirred at −78° C. for 35 min, then asolution of chlorodicyclohexylphosphine (2.21 g, 9.51 mmol) in THF (30mL) was added dropwise to the reaction vessel. The reaction mixture wasstirred at −78° C. and allowed to warm slowly to room temperatureovernight. The reaction was then quenched with saturated aqueous NH₄Cl(30 mL), diluted with ether (200 mL), and poured into a separatoryfunnel. The layers were separated and the aqueous phase was extractedwith ether (50 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered, and concentrated to give a whitesolid. The crude material was recrystallized from degassed, hot ethanolunder an argon atmosphere to afford 2.25 g (29% overall yield for 3steps) of a white solid: mp 110° C.; ¹H NMR (300 MHz, CDCl₃) δ 7.54 (d,1H, J=6.8 Hz), 7.26-7.40 (m, 4H), 7.02-7.05 (m, 1H), 6.93-6.98 (m, 3H),2.44 (s, 6H), 1.98-2.05 (m, 1H), 1.40-1.82 (m, 11 H), 0.75-1.38 (m, 10H); ¹³C NMR (125 MHz, CDCl₃) δ 151.5, 149.8, 149.5, 135.8, 135.5, 135.3,132.7, 132.4, 130.54, 130.49, 128.5, 128.1, 125.8, 120.6, 117.3, 43.2,36.8, 36.7, 33.5, 33.4, 30.9, 30.8, 30.6, 30.4, 29.8, 29.7, 28.5, 27.6,27.54, 27.46, 27.3, 27.2, 26.7, 26.4 (observed complexity due to P—Csplitting; definitive assignments have not yet been made); ³¹P NMR(121.5 MHz, CDCl₃) δ −9.2; IR (neat, cm⁻¹) 2922, 1444, 745. Anal Calcdfor C₂₆H₃₆NP: C, 79.35; H, 9.22. Found: C, 79.43; H, 9.48.

General procedure for the palladium-catalyzed amination of arylchlorides: An oven-dried Schlenk tube or test tube fitted with a rubberseptum was purged with argon and charged withtris(dibenzylidineacetone)dipalladium (0.005 mmol, 1 mol % Pd), ligand 2(0.015 mmol, 1.5 mol %), and NaOt-Bu (1.4 mmol). The tube was purgedwith argon, and toluene (2.0 mL), the aryl chloride (1.0 mmol) and theamine (1.2 mmol) were added. The mixture was stirred in an 80° C. oilbath until the starting aryl chloride had been completely consumed asjudged by GC analysis. The reaction mixture was then cooled to roomtemperature, diluted with ether (20 mL), filtered through celite andconcentrated in vacuo. The crude material was then purified by flashchromatography on silica gel.N-(4-methylphenyl)-p-anisidine.¹³

The general procedure except using a reaction temperature of 100° C.gave 198 mg (93%) of a tan solid: mp 80-81° C. (lit.¹³ mp 84-85° C.). ¹HNMR (300 MHz, CDCl₃) δ 6.98-7.05 (m, 4H), 6.80-6.86 (m, 4H), 5.37 (s, br1H), 3.76 (s, 3H), 2.26 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 154.8,142.4, 136.7, 129.7, 129.3, 121.1, 116.6, 114.7, 55.6, 20.5; IR (neat,cm⁻¹) 3416, 2910, 1513, 1304, 815.

N-benzyl-p-toluidine.¹⁴

The general procedure except using 1 as the ligand, and 1.5 equiv ofbenzyl amine, gave 177 mg (90%) of a pale yellow oil: ¹H NMR (250 MHz,CDCl₃) δ 7.25-7.39 (m, 5H), 6.98 (d, 2H, J=8.1 Hz), 6.56 (d, 2H, J=8.5Hz), 4.31 (s, 2H), 3.90 (br s, 1H), 2.23 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 145.9, 139.7, 129.7, 128.5, 127.4, 127.1, 126.7, 113.0, 48.6,20.3; IR (neat, cm⁻¹) 3416, 3026, 1521, 807.

N-(4-Cyanophenyl)morpholine.¹¹

An oven-dried resealable Schlenk tube was purged with argon and chargedwith Pd₂(dba)₃ (11.5 mg, 0.025 mmol, 5 mol % Pd), 2 (14.8 mg, 0.075mmol, 7.5 mol %), NaOt-Bu (68 mg, 0.71 mmol) and 4-chlorobenzonitrile(69 mg, 0.50 mmol). The tube was purged with argon then DME (0.5 mL) andmorpholine (53 μL, 0.61 mmol) were added through a rubber septum. Theseptum was removed, the tube was sealed with a teflon screw cap and themixture was stirred at room temperature for 26 h, then diluted withEtOAc, filtered through celite and concentrated in vacuo. The crudematerial was purified by flash chromatography on silica gel to afford 91mg (96%) of a tan solid.

Amination using 0.05 mol % Pd. An oven-dried resealable Schlenk tube waspurged with argon and charged with Pd₂(dba)₃ (2.3 mg, 0.0025 mmol, 0.05mol % Pd), ligand 2 (2.9 mg, 0.0075 mmol, 0.075 mol %), and NaOt-Bu(1.34 g, 13.9 mmol). Toluene (10 mL), di-n-butylamine (2.00 mL, 11.9mmol), and 4-chlorotoluene (1.18 mL, 10.0 mmol) were added and themixture was degassed using three freeze-pump-thaw cycles. The reactionvessel was placed under argon, sealed with a teflon screw cap, andstirred in a 100° C. oil bath for 20 h after which time GC analysisshowed the aryl halide had been completely consumed. The reactionmixture was cooled to room temperature, diluted with ether (100 mL) andextracted with 1 M HCl (3×100 mL). The combined aqueous acid phase wasbasified with 3N NaOH, then extracted with ether (3×150 mL). Theethereal extracts were dried over anhydrous sodium sulfate, filtered andconcentrated to afford 2.01 g (95%) of di-n-butyltoluidine⁶ as a paleyellow oil.General procedure for the room-temperature palladium-catalyzed aminationof aryl bromides: An oven-dried resealable Schlenk tube was purged withargon and charged with Pd₂(dba)₃ (0.005-0.025 mmol, 1-5 mol % Pd),ligand 2 (0.015-0.075 mmol, 1.5-7.5 mol %), and NaOt-Bu (1.4 mmol) [seeTable 1 for amount of Pd and ligand used]. The tube was purged withargon, fitted with a rubber septum and then DME (0.5 mL-1.0 mL), thearyl bromide (1.0 mmol) and the amine (1.2 mmol) were added via syringe.The septum was removed, the tube was sealed with a teflon screw cap andthe mixture was stirred at room temperature for 24 h. The reactionmixture was then diluted with ether (20 mL), filtered through celite andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel.2,6-Dimethyl-N-(n-hexyl)aniline.

The general procedure was conducted with with 0.5 mmol of aryl bromideand afforded 90 mg (87%) of a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ6.98 (d, 2H, J=7.5 Hz), 6.79 (t, 1H, J=7.5 Hz), 2.97 (t, 2H, J=7.2 Hz),2.94-2.99 (br, 1H), 2.28 (s, 6H), 1.52-1.60 (m, 2H), 1.28-1.41 (m, 6H),0.89 (t, 3H, J=6.8 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 146.5, 129.1, 128.8,121.5, 48.7, 31.7, 31.2, 26.9, 22.6, 18.5, 14.0; IR (neat, cm⁻¹) 3384,2926, 1472, 1256, 1219, 762. Anal Calcd for C₁₄H₂₃N: C, 81.89; H, 11.29.Found: C, H.

N-(2,5-Dimethylphenyl)morpholine.

The general procedure was conducted at 2.0 M concentration and afforded185 mg (95%) of a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.06 (d, 1H,J=7.7 Hz), 6.80-6.82 (m, 2H), 3.84 (t, 4H, J=4.6 Hz), 2.89 (t, 4H, J=4.6Hz), 2.31 (s, 3H), 2.26 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 151.1,136.2, 131.0, 129.3, 124.0, 119.7, 67.5, 52.3, 21.1, 17.4; IR (neat,cm⁻¹) 2955, 2851, 1505, 1242, 1117, 807. Anal Calcd for C₁₂H₁₇NO: C,75.35; H, 8.96. Found: C, H.

N-(4-carbomethoxyphenyl)morpholine.¹⁵

The general procedure was conducted with 0.5 mmol of aryl bromide exceptusing K₃PO₄ in place of NaOt-Bu at 80° C., EtOAc as the workup solventand gave 89 mg (80%) of a colorless solid: mp 152-154° C. (lit.¹⁵ mp157-160° C.). ¹H NMR (300 MHz, CDCl₃) δ 7.94 (d, 2H, J=8.6 Hz), 6.86 (d,2H, J=8.8 Hz), 3.87 (s, 3H), 3.86 (t, 4H, J=4.8 Hz), 3.29 (t, 4H, J=4.8Hz); ¹³C NMR (125 MHz, CDCl₃) δ 167.0, 154.2, 131.2, 120.4, 113.5, 66.6,51.6, 47.8; IR (neat, cm⁻¹) 2968, 1698, 1289, 1116, 768. Anal Calcd forC₁₂H₁₅NO₃: C, 65.14; H, 6.83. Found: C, H.

N-(4-acetylphenyl)morpholine.¹⁶

The general procedure except using Pd(OAc)₂, K₃PO₄ in place ofPd₂(dba)₃, NaOtBu, at a reaction temperature of 80° C., and 1/1Et₂O/EtOAc as the workup solvent gave 169 mg (82%) of a pale yellowsolid: m.p. 93-94° C. (lit.¹⁴ mp 97-98° C.). ¹H NMR (300 MHz, CDCl₃) δ7.89 (d, 2H, J=9.1 Hz), 6.87 (d, 2H, J=9.1 Hz), 3.86 (t, 4H, J=4.8 Hz),3.31 (t, 4H, J=5.1 Hz), 2.54 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 196.4,154.1, 130.2, 128.1, 113.2, 66.5, 47.5, 26.0; IR (neat, cm⁻¹) 2972,1660, 1243, 1119, 818. Anal Calcd for C₁₂H₁₅NO₂: C, 70.22; H, 7.37.Found: C, 70.31; H, 7.22.

Aminations with dicyclohexylphenylphosphine as the supporting ligand.The coupling of 4-chlorotoluene and di-n-butylamine following thegeneral procedure for catalytic amination of aryl chlorides usingdicyclohexylphenylphosphine in place of 2 led to 96% conversion (17% GCyield) in 12 h. In the same amount of time, the reaction using ligand 2was complete, affording a 97% isolated yield of the desired product. Thecoupling of 2-bromo-p-xylene and morpholine following the roomtemperature procedure above, replacing 2 withdicyclohexylphenylphosphine (1.5 L/Pd), led to 2.5% consumption of thestarting aryl bromide, with a trace amount of product detected (GC).When a ratio of 3 L/Pd was used, no reaction was observed.

General procedure for the room-temperature Suzuki coupling of arylhalides: An oven-dried resealable Schlenk tube was purged with argon andcharged with Pd(OAc)₂ (0.02 mmol, 2 mol %), ligand 2 (0.03 mmol, 3 mol%), the boronic acid (1.5 mmol), and cesium fluoride (3.0 mmol). Thetube was purged with argon, and dioxane (3 mL) and the aryl halide (1.0mmol) were added through a rubber septum. The septum was removed, thetube was sealed with a teflon screw cap and the mixture was stirred atroom temperature until the starting aryl halide had been completelyconsumed as judged by GC analysis. The reaction mixture was then dilutedwith ether (20 mL) and poured into a separatory funnel. The mixture waswashed with 1 M NaOH (20 mL), and the layers were separated. The aqueouslayer was extracted with ether (20 mL), and the combined organic layerswere dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo. The crude material was then purified by flash chromatographyon silica gel.3,5-Dimethylbiphenyl.¹⁷

The general procedure using 1 mol % Pd(OAc)₂ and 1.5 mol % ligand 2 gave171 mg (94%) of a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.57 (d, 2H,J=6.8 Hz), 7.42 (t, 2H, J=7.2 Hz), 7.31-7.34 (m, 1H), 7.21 (s, 2H), 7.00(s, 1H), 2.38 (s, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 141.5, 141.3, 138.2,128.9, 128.6, 127.2, 127.0, 125.1, 21.4; IR (neat, cm⁻¹) 3030, 1602,849, 760. Anal Calcd for C₁₄H₁₄: C, 92.26; H, 7.74. Found: C, 91.98; H,8.02.

2,5,3′-Trimethylbiphenyl.¹⁸

The general procedure gave 192 mg (98%) of a colorless oil whichcontained 4% 3,3′-dimethylbiphenyl as determined by ¹H NMR: ¹H NMR (300MHz, CDCl₃) δ 7.25-7.28 (m, 1H), 7.04-7.16 (m, 6H), 2.39 (s, 3H), 2.34(s, 3H), 2.23 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 142.1, 141.9, 137.5,135.0, 132.1, 130.5, 130.2, 129.9, 127.85, 127.80, 127.3, 126.2, 21.4,20.9, 19.9; IR (neat, cm⁻¹) 2949, 1451, 811, 703. Anal Calcd for C₁₅H₁₅:C, 92.26; H, 7.74. Found: C, 92.34; H, 7.66.

4-Acetyl-3′-methylbiphenyl.¹⁹

The general procedure gave 190 mg (90%) of a white solid: mp 84-86° C.(lit.¹⁹ mp 92° C.). ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, 2H, J=8.5 Hz),7.68 (d, 2H, J=8.5 Hz), 7.33-7.44 (m, 3H), 7.20-7.26 (m, 1H), 2.64 (s,3H), 2.43 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.6, 145.8, 139.7,138.5, 135.7, 128.9, 128.8, 127.9, 127.1, 124.3, 26.5, 21.4; IR (neat,cm⁻¹) 3019, 1683, 1270, 787. Anal Calcd for C₁₅H₁₄O: C, 85.68; H, 6.71.Found: C, 85.79; H, 6.92

Methyl 4-phenylbenzoate.²⁰

The general procedure (except using water for the aqueous workup inplace of 1 M aqueous NaOH) gave 193 mg (91%) of a white solid: mp 113°C. (lit.²⁰ mp 117-118° C.). ¹H NMR (300 MHz, CDCl₃) δ 8.11 (d, 2H, J=8.3Hz), 7.61-7.68 (m, 4H), 7.39-7.49 (m, 3H), 3.94 (s, 3H); ¹³C NMR (125MHz, CDCl₃) δ 166.9, 145.5, 139.9, 130.0, 128.8, 128.1, 127.2, 126.9,52.0; IR (neat, cm⁻¹) 2945, 1710, 1270, 1112, 749. Anal Calcd forC₁₄H₁₃O₂: C, 78.85; H, 6.14. Found: C, 79.04; H, 6.16.

4-Hexylanisole.²¹

An oven-dried resealable Schlenk tube was capped with a rubber septum,cooled under an argon purge, charged with 1-hexene (0.19 mL, 1.5 mmol),and cooled to 0° C. A solution of 9-BBN in THF (3 mL, 1.5 mmol, 0.5 M)was added, the flask was stirred at 0° C. for 15 min, then warmed toroom temperature and stirred for 5 h. 4-Chloroanisole (0.12 mL, 1.0mmol) was added, the septum was removed, and palladium acetate (4.4 mg,0.02 mmol, 2 mol %), ligand 2 (11.9 mg, 0.03 mmol, 3 mol %), and cesiumfluoride (456 mg, 3.0 mmol) were added under a stream of argon. Theseptum was replaced and the flask was purged with argon for 30 s.Dioxane (2 mL) was added, the septum was removed, the tube was sealedwith a teflon screw cap, and the mixture was stirred at rt for 2 min.The reaction mixture was then heated to 50° C. with stirring for 22 h,at which time GC analysis showed the aryl chloride had been completelyconsumed. The mixture was cooled to room temperature, diluted with ether(20 mL), and poured into a separatory funnel. The mixture was washedwith 1 M aqueous NaOH (20 mL), the layers were separated, and theaqueous phase was extracted with ether (20 mL). The combined organiclayers were dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. The crude material was purified by flashchromatography to afford 170 mg (89%) of a colorless oil:

¹H NMR (300 MHz, CDCl₃) δ 7.09 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.6Hz), 3.78 (s, 3H), 2.54 (t, 2H, J=7.5 Hz), 1.54-1.60 (m, 2H), 1.28-1.35(m, 6H), 0.88 (t, 3H, J=6.8 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 157.6,135.0, 129.2, 113.6, 55.2, 35.0, 31.73, 31.70, 28.9, 22.6, 14.1; IR(neat, cm⁻¹) 2926, 1513, 1243, 1038, 822. Anal Calcd for C₁₃H₂₀O: C,81.20; H, 10.48. Found: C, 81.19; H, 10.62.

General procedure for K₃PO₄ promoted Suzuki coupling of aryl chlorides:An oven-dried resealable Schlenk tube was purged with argon and chargedwith Pd(OAc)₂ (0.01 mmol, 0.5 mol %), ligand 2 (0.015 mmol, 0.75 mol %),the boronic acid (3.0 mmol), and potassium phosphate (4.0 mmol). Thetube was purged with argon, and dioxane (6 mL) and 4-chlorotoluene (2.0mmol) were added through a rubber septum. The septum was removed, thetube was sealed with a teflon screw cap and the mixture was stirred atroom temperature for 2 min, then heated to 100° C. with stirring untilthe starting aryl chloride had been completely consumed as judged by GCanalysis. The reaction mixture was then cooled to room temperature,diluted with ether (20 mL) and poured into a separatory funnel. Themixture was washed with 1 M NaOH (20 mL), and the layers were separated.The aqueous layer was extracted with ether (20 mL), and the combinedorganic layers were dried over anhydrous magnesium sulfate, filtered,and concentrated in vacuo. The crude material was then purified by flashchromatography on silica gel.

4-Methoxybiphenyl.²²

The general procedure gave 347 mg (94%) of a white solid: mp 83-84° C.(lit.²² mp 87° C.); ¹H NMR (250 MHz, CDCl₃) δ 7.52-7.58 (m, 4H), 7.42(t, 2H, J=7.8 Hz), 7.26-7.38 (m, 1H), 6.97 (d, 2H, J=6.7 Hz), 3.86 (s,3H); ¹³C NMR (125 MHz, CDCl₃) δ 159.1, 140.8, 133.7, 128.7, 128.1,126.7, 126.6, 114.2, 55.3; IR (neat, cm⁻¹) 3003, 1251, 1034, 834, 760.Anal Calcd for C₁₃H₁₂O: C, 84.75; H, 6.57. Found: C, 85.06; H, 6.72.

4-Methylbiphenyl.²³

The general procedure gave 319 mg (95%) of a white solid: mp 44-46° C.(lit.²³ mp 49-50° C.); ¹H NMR (250 MHz, CDCl₃) δ 7.57 (d, 2H, J=8.8 Hz),7.39-7.51 (m, 4H), 7.23-7.35 (m, 3H), 2.40 (s, 3H); ¹³C NMR (125 MHz,CDCl₃) δ 141.2, 138.4, 136.9, 129.4, 128.7, 126.94, 126.92, 21.0; IR(neat, cm⁻¹) 3030, 1486, 822, 753. Anal Calcd for C₁₃H₁₂: C, 92.81; H,7.19. Found: C, 92.86; H, 7.15.

4-Methyl-2′-methoxybiphenyl.²⁴

The general procedure was conducted on a 1 mmol scale using 1 mol %Pd(OAc)₂, 1.5 mol % ligand 2, and 3 eq CsF in place of K₃PO₄ to give 196mg (99%) of a white solid, mp 74-75° C. (lit.²⁴ mp 70-72° C.); ¹H NMR(250 MHz, CDCl₃) δ 7.42 (d, 2H, J=8.1 Hz), 7.21-7.33 (m, 4H), 7.16-7.04(m, 2H), 3.81 (s, 3H), 2.39 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 156.5,136.5, 135.6, 130.7, 129.4, 128.6, 128.3, 120.8, 111.2, 55.5, 21.2; IR(neat, cm⁻¹) 2964, 1227, 1023, 757. Anal Calcd for C₁₄H₁₄O: C, 84.81; H,7.12. Found: C, 84.94; H, 7.36.

Suzuki coupling with dicyclohexylphenylphosphine as the supportingligand. Two coupling reactions of 4-chlorotoluene with phenylboronicacid using the general procedures for Suzuki couplings described abovewere carried out with dicyclohexylphenylphosphine (2 L/Pd) in place of2. The reaction conducted at room temperature with CsF as the baseproceeded to 10% conversion (5% GC yield) after 2 days, while thereaction at 100° C. with K₃PO₄ as the base proceeded to 27% conversion(18% GC yield) in 2 days.

2-Methyl-4-(3,5-xylyl)-3-pentanone.

An oven-dried resealable Schlenk tube was charged with NaHMDS (238 mg,1.3 mmol) under nitrogen in a Vacuum Atmospheres glovebox. The tube wascapped with a teflon screw cap and removed from the glovebox. Thescrewcap was removed and Pd₂(dba)₃ (13.7 mg, 0.015 mmol, 3 mol % Pd) and2 (14.1 mg, 0.036 mmol, 3.6 mol %) were added under a stream of argon.The tube was capped with a rubber septum and toluene (3 mL) was addedwith stirring. The flask was then charged with 5-bromo-m-xylene (0.135mL, 1.0 mmol), 2-methyl-3-pentanone (0.15 mL, 1.2 mmol), and additionaltoluene (3 mL). The septum was replaced with a teflon screw cap and thereaction mixture was stirred at room temperature for 22 h until thestarting aryl bromide had been completely consumed as judged by GCanalysis. The reaction was quenched with 5 mL of saturated aqueousNH₄Cl, diluted with ether (20 mL), and poured into a separatory funnel.The layers were separated, and the aqueous phase was extracted withether (10 mL). The combined organic layers were dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified by flash chromatography on silica gel to give 163mg (80%) of a colorless oil. GC and NMR analysis showed the materialobtained was a mixture of the desired product and a regioisomercontaining the aryl group at the 2-position of the ketone (46/1 ratio byGC analysis; 40/1 ratio by ¹H NMR analysis). NMR data are given for themajor product only. ¹H NMR (250 MHz, CDCl₃) δ 6.88 (s, 1H), 6.81 (s,2H), 3.83 (q, 1H, J=6.9 Hz), 2.68 (p, 1H, J=6.9 Hz), 2.29 (s, 6H), 1.34(d, 3H, J=6.9 Hz), 1.07 (d, 3H, J=7.0 Hz), 0.92 (d, 3H, J=6.6 Hz); ¹³CNMR (125 MHz, CDCl₃) δ 214.7, 140.7, 138.3, 128.6, 125.7, 50.9, 39.0,21.2, 19.3, 18.2, 18.1; IR (neat, cm⁻¹) 2972, 1710, 1101, 849. Anal (forthe mixture) Calcd for C₁₄H₂₀O: C, 82.3; H, 9.87. Found: C, 82.09; H,9.85.

1,1-Bis(4-methylphenyl)-3-methyl-2-butanone.

An oven-dried Schlenk tube was cooled under an argon purge and chargedwith Pd₂(dba)₃ (13.7 mg, 0.015 mmol, 3 mol % Pd), 2 (14.1 mg, 0.036mmol, 3.6 mol %), and NaOtBu (211 mg, 2.2 mmol). The flask was purgedwith argon, and toluene (3 mL) was added with stirring. The flask wasthen charged with 4-chlorotoluene (0.24 mL, 2.0 mmol),3-methyl-2-butanone (0.105 mL, 1.0 mmol), and additional toluene (3 mL).The reaction mixture was stirred at room temperature for 2 min, thenheated to 80° C. with stirring for 22 h at which time GC analysis showedthe starting aryl chloride had been completely consumed. The reactionmixture was cooled to room temperature, quenched with saturated aqueousNH₄Cl (5 mL), diluted with ether (20 mL), and poured into a separatoryfunnel. The layers were separated and the aqueous phase was extractedwith ether (10 mL). The combined organic fractions were dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo. Thecrude material was purified by flash chromatography on silica gel togive 210 mg (79%) of a white solid: mp 48-51° C.; ¹H NMR (300 MHz,CDCl₃) δ 7.00-7.18 (m, 8H), 5.22 (s, 1H), 2.79 (p, 1H, J=6.8 Hz), 2.31(s, 6H), 1.10 (d, 6H, J=6.8 Hz); ¹³C NMR (125 MHz, CDCl₃) δ 212.3,136.6, 135.8, 129.24, 129.16, 128.9, 128.7, 61.4, 40.7, 21.0, 18.6; IR(neat, cm⁻¹) 2972, 1718, 1513, 1038, 803. Anal Calcd for C₁₄H₂₀O: C,85.67; H, 8.32. Found: C, 86.02; H, 8.59.

REFERENCES FOR SUPPORTING INFORMATION FOR EXAMPLE 1

-   (1) Parham, W. E.; Piccirilli, R. M. J. Org. Chem. 1977, 42,    257-260.-   (2) Thompson, W. J.; Gaudino, J. J. Org. Chem. 1984, 49, 5237-5243.-   (3) Zhang, X.; Mashima, K.; Koyano, K.; Sayo, N.; Kumobayashi, H.;    Akutagawa, S.; Takaya, H. J. Chem. Soc. Perkin Trans. 1 1994,    2309-2322.-   (4) Miyashita, A.; Takaya, H.; Souchi, T.; Noyori, R. Tetrahedron    1984, 40, 1245-1253.-   (5) Hegedus, L. S. in Organometallics in Synthesis Schlosser, M.    Ed., John Wiley and Sons, West Sussex, England, 1994, p 448.-   (6) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133-1135.-   (7) Marcoux, J. -F.; Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997,    62, 1568-1569.-   (8) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,    6054-6058.-   (9) Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,    7215-7216.-   (10) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38,    6359-6362.-   (11) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62,    1264-1267.-   (12) Lauer, M.; Wulff, G. J Organomet. Chem. 1983, 256, 1-9.-   (13) Abe, M.; Takahashi, M. Synthesis 1990, 939-942.-   (14) Watanabe, Y.; Tsuji, Y.; Ige, H.; Ohsugi, Y.; Ohta, T. J. Org.    Chem. 1984, 49, 3359-3363.-   (15) Behringer, H.; Heckmaier, P. Chem. Ber. 1969, 102, 2835-2850.-   (16) Kotsuki, H.; Kobayashi, S.; Matsumoto, K.; Suenaga, H.;    Nishizawa, H. Synthesis 1990, 1147-1148.-   (17) Häfelinger, G.; Beyer, M.; Burry, P.; Eberle, B.; Ritter, G.;    Westermayer, G.; Westermayer, M. Chem. Ber. 1984, 117, 895-903.-   (18) Novrocik, J.; Novrocikova, M.; Titz, M. Coll. Czech. Chem.    Commun. 1980, 3140-3149.-   (19) Wirth, H. O.; Kern, W.; Schmitz, E. Makromol. Chem. 1963, 68,    69-99.-   (20) Barba, I.; Chinchilla, R.; Gomez, C. Tetrahedron 1990, 46,    7813-7822.-   (21) Skraup, S.; Nieten, F. Chem. Ber. 1924, 1294-1310.-   (22) Darses, S.; Jeffery, T.; Brayer, J. -L.; Demoute, J. -P.;    Genet, J. -P. Bull. Soc. Chim. Fr. 1996, 133, 1095-1102.-   (23) Rao, M. S. C.; Rao, G. S. K. Synthesis 1987, 231-233.-   (24) Hatanaka, Y. Goda, K. -i.; Okahara, Y.; Hiyama, T. Tetrahedron    1994, 50, 8301-8316.

Example 2 Synthesis of N-(2,5-Dimethylphenyl)-N-methylaniline

An oven-dried test tube was purged with argon and charged with Pd₂(dba)₃(4.6 mg, 0.005 mmol, 1.0 mol % Pd), 2 [Example 1] (6.0 mg, 0.015 mmol,1.5 mol %), and NaOt-Bu (135 mg, 1.40 mmol). The test tube was fittedwith a septum, then toluene (2.0 mL), N-methylaniline (135 μL, 1.25mmol), and 2-chloro-p-xylene (135 μL, 1.01 mmol) were added. The mixturewas stirred at 80° C. for 13 h, then cooled to room temperature, dilutedwith ether (20 mL), filtered and concentrated. The crude material waspurified by flash chromatography on silica gel to afford 202 mg (95%) ofa colorless oil.

Example 3 Synthesis of Di-n-butyl-p-toluidine

An oven-dried resealable Schlenk tube was purged with argon and chargedwith Pd₂(dba)₃ (2.3 mg, 0.0025 mmol, 0.05 mol % Pd), 2 [Example 1] (2.9mg, 0.0075 mmol, 0.075 mol %), and NaOt-Bu (1.34 g, 13.9 mmol). Toluene(10 mL), di-n-butylamine (2.00 mL, 11.9 mmol), and 4-chlorotoluene (1.18mL, 10.0 mmol) were added and the mixture was degassed using threefreeze-pump-thaw cycles. The reaction vessel was placed under argon,sealed with a teflon screw cap, and stirred in a 100° C. oil bath for 20h after which time GC analysis showed the aryl halide had beencompletely consumed. The reaction mixture was cooled to roomtemperature, diluted with ether (100 mL) and extracted with 1 M HCl(3×100 mL). The combined aqueous acid phase was basified with 3N NaOH,then extracted with ether (3×150 mL). The ethereal extracts were driedover anhydrous sodium sulfate, filtered and concentrated to afford 2.01g (95%) of a pale yellow oil.

Example 4 Synthesis of N-(4-Cyanophenyl)morpholine

An oven-dried resealable Schlenk tube was purged with argon and chargedwith Pd₂(dba)₃ (11.5 mg, 0.025 mmol, 5 mol % Pd), 2 [Example 1] (14.8mg, 0.075 mmol, 7.5 mol %), NaOt-Bu (68 mg, 0.71 mmol) and4-chlorobenzonitrile (69 mg, 0.50 mmol). The tube was purged with argonthen DME (0.5 mL) and morpholine (53 μL, 0.61 mmol) were added through arubber septum. The septum was removed, the tube was sealed with a teflonscrew cap and the mixture was stirred at room temperature for 26 h. Thereaction was then diluted with EtOAc (20 mL), filtered through celiteand concentrated in vacuo. The crude material was purified by flashchromatography on silica gel to afford 91 mg (96%) of a tan solid.

Example 5 Synthesis of N-(2,5-Dimethylphenyl)morpholine

An oven-dried resealable Schlenk tube was purged with argon and chargedwith Pd₂(dba)₃ (13.9 mg, 0.015 mmol, 3.0 mol % Pd), 2 [Example 1] (17.9mg, 0.045 mmol, 4.5 mol %), and NaOt-Bu (140 mg, 1.4 mmol). The tube waspurged with argon, fitted with a rubber septum and then DME (0.5 mL),2-bromo-p-xylene (140 μL, 1.01 mmol) and morpholine (105 μL, 1.2 mmol)were added via syringe. The septum was removed, the tube was sealed witha teflon screw cap and the mixture was stirred at room temperature for24 h. The reaction mixture was then diluted with ether (20 mL), filteredthrough celite and concentrated in vacuo. The crude material waspurified by flash chromatography on silica gel to afford 185 mg (95%) ofa colorless oil.

Example 6 Synthesis of N-(4-Carbomethoxyphenyl)morpholine

An oven-dried resealable Schlenk tube was purged with argon and chargedwith Pd₂(dba)₃ (2.3 mg, 0.0025 mmol, 1.0 mol % Pd), 2 [Example 1] (3.0mg, 0.0076 mmol, 1.5 mol %), K₃PO₄ (150 mg, 0.71 mmol), and methyl4-bromobenzoate (108 mg, 0.50 mmol). The tube was purged with argon,fitted with a rubber septum and then DME (1.0 mL) and morpholine (55 μL,0.63 mmol) were added. The septum was removed, the tube was sealed witha teflon screw cap and the mixture was stirred at 80° C. for 24 h. Thereaction mixture was then cooled to room temperature, diluted with EtOAc(20 mL), filtered through celite and concentrated in vacuo. The crudematerial was purified by flash chromatography on silica gel to afford 89mg (80%) of a colorless solid.

Example 7 Synthesis of N-benzyl-p-toluidine

An oven dried Schlenk tube was purged with argon and charged withPd₂(dba)₃ (4.6 mg, 0.005 mmol, 1.0 mol % Pd), Cy-BINAP (9.6 mg, 0.015mmol, 1.5 mol %), and NaOtBu (135 mg, 1.4 mmol). The tube was purgedwith argon and charged with toluene (2 mL), 4-chlorotoluene (0.12 mL,1.0 mmol), and benzylamine (0.165 mL, 1.5 mmol). The mixture was heatedto 100° C. with stirring until the starting aryl chloride had beencompletely consumed as judged by GC analysis. The reaction mixture wascooled to room temperature, diluted with ether (20 mL), filtered throughcelite, and concentrated in vacuo. The crude material was then purifiedby flash chromatography on silica gel to give 177 mg (90%) of a paleyellow oil.

Example 8 Synthesis of 3,5-dimethylbiphenyl via Suzuki Coupling

An oven dried resealable Schlenk tube was purged with argon and chargedwith palladium acetate (2.2 mg, 0.01 mmol, 1 mol %), ligand 2 [Example1] (5.9 mg, 0.015 mmol, 1.5 mol %), phenylboron dihydroxide (183 mg, 1.5mmol), and cesium fluoride (456 mg, 3.0 mmol). The tube was purged withargon, and dioxane (3 mL) and 5-bromo-m-xylene (0.135 mL, 1.0 mmol) wereadded through a rubber septum. The septum was removed, the tube wassealed with a teflon screw cap and the mixture was stirred at roomtemperature until the starting aryl bromide had been completely consumedas judged by GC analysis. The reaction mixture was then diluted withether (20 mL) and poured into a separatory funnel. The mixture waswashed with 1M NaOH (20 mL), and the layers were separated. The aqueouslayer was extracted with ether (20 mL), and the combined organicextracts were dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. The crude material was then purified by flashchromatography on silica gel to give 171 mg (94%) of a colorless oil.

Example 9 Synthesis of 4-methylbiphenyl via Suzuki Coupling

An oven dried resealable Schlenk tube was purged with argon and chargedwith palladium acetate (4.4 mg, 0.02 mmol, 2 mol %), ligand 2 [Example1] (11.9 mg, 0.03 mmol, 3 mol %), phenylboron dihydroxide (183 mg, 1.5mmol), and cesium fluoride (456 mg, 3.0 mmol). The tube was purged withargon, and dioxane (3 mL) and 4-chlorotoluene (0.12 mL, 1.0 mmol) wereadded through a rubber septum. The septum was removed, the tube wassealed with a teflon screw cap and the mixture was stirred at roomtemperature until the starting aryl chloride had been completelyconsumed as judged by GC analysis. The reaction mixture was then dilutedwith ether (20 mL) and poured into a separatory funnel. The mixture waswashed with 1M NaOH (20 mL), and the layers were separated. The aqueouslayer was extracted with ether (20 mL), and the combined organicextracts were dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. The crude material was then purified by flashchromatography on silica gel to give 157 mg (93%) of a glassy solid.

Example 10 Synthesis of 3-methyl-4′-acetylbiphenyl via Suzuki Coupling

An oven dried resealable Schlenk tube was purged with argon and chargedwith palladium acetate (4.4 mg, 0.02 mmol, 2 mol %), ligand 2 [Example1] (11.9 mg, 0.03 mmol, 3 mol %), 3-methylphenylboronic acid (204 mg,1.5 mmol), and cesium fluoride (456 mg, 3.0 mmol). The tube was purgedwith argon, and dioxane (3 mL), and 4-chloroacetophenone (0.13 mL, 1.0mmol) were added through a rubber septum. The septum was removed, thetube was sealed with a teflon screw cap and the mixture was stirred atroom temperature until the starting aryl chloride had been completelyconsumed as judged by GC analysis. The reaction mixture was then dilutedwith ether (20 mL) and poured into a separatory funnel. The mixture waswashed with 1M NaOH (20 mL), and the layers were separated. The aqueouslayer was extracted with ether (20 mL), and the combined organicextracts were dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. The crude material was then purified by flashchromatography on silica gel to give 195 mg (93%) of a white solid.

Example 11 Synthesis of 4-methoxybiphenyl via Suzuki Coupling

An oven dried resealable Schlenk tube was purged with argon and chargedwith palladium acetate (2.2 mg, 0.01 mmol, 0.5 mol %), ligand 2 [Example1] (5.9 mg, 0.015 mmol, 0.75 mol %), phenylboron dihydroxide (366 mg,3.0 mmol), and potassium phosphate (850 mg, 4.0 mmol). The tube waspurged with argon, and dioxane (6 mL), and 4-chloroanisole (0.24 mL, 2.0mmol) were added through a rubber septum. The septum was removed, thetube was sealed with a teflon screw cap and the mixture was stirred atroom temperature for two minutes, then heated to 100° C. with stirringuntil the starting aryl chloride had been completely consumed as judgedby GC analysis. The reaction mixture was then diluted with ether (40 mL)and poured into a separatory funnel. The mixture was washed with 1M NaOH(40 mL), and the layers were separated. The aqueous layer was extractedwith ether (40 mL), and the combined organic extracts were dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo. Thecrude material was then purified by flash chromatography on silica gelto give 347 mg (94%) of a white solid.

Example 12 Synthesis of 2-amino-2′-bromo-1,1′-binaphthyl benzophenoneimine

An oven-dried 100 mL round-bottom flask was fitted with a refluxcondenser, purged with argon and charged with2,2′-dibromo-1,1′-binaphthyl (5.0 g, 12.1 mmol), benzophenone imine (2.9g, 15.7 mmol), NaOt-Bu (1.7 g, 18.0 mmol), Pd₂(dba)₃ (110 mmol, 0.12mmol), bis(2-(diphenylphosphino)phenyl)ether (129 mg, 0.24 mmol), andtoluene (50 mL). The mixture was stirred for 18 hours at 100° C. thencooled to room temperature and two-thirds of the solvent was removedunder reduced pressure. Ethanol (25 mL) and water (3 mL) were added tothe resulting mixture. The yellow crystals were collected on a Büchnerfunnel and washed with ethanol (10 mL) to afford 5.7 g (92%) of crudematerial which was used in the following Example without furtherpurification.

Example 13 Synthesis of 2-amino-2′-bromo-1,1′-binaphthyl

The crude imine from Example 12 (3.0 g, 5.9 mmol) was suspended indichloromethane (100 mL) in a 300 mL round bottom flask. Concentratedhydrochloric acid (1.5 mL, 17.6 mmol) was added to the suspension whichbecame homogeneous within 15 min. The reaction mixture was stirred for18 hours at room temperature during which time a precipitate formed. Themixture was them treated with 1M NaOH (25 mL), and the layers wereseparated. The aqueous layer was extracted with additionaldichloromethane (10 mL). The combined organic layers were washed withbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. The crude material was then purified by flashchromatography on silica gel to give 1.5 g (73%) of colorless crystals.

Example 14 Synthesis of 2-N,N-dimethylamino-2′-bromo-1,1′-binaphthyl

A 20 mL round-bottom flask was charged with amine from Example 13 (480mg, 1.4 mmol), iodomethane (0.25 mL, 4.2 mmol), sodium carbonate (318mg, 3.0 mmol), and DMF (8 mL), and then purged with argon. The mixturewas heated to 50° C. and stirred until the starting material had beencompletely consumed. The reaction mixture was diluted with ether (5 mL)and water (1 mL) and then passed through a plug of silica gel. Thefiltrate was dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo to give 473 mg (91%) of colorless crystals.

Example 15 Synthesis of2-N,N-dimethylamino-2′-diphenylphosphino-1,1′-binaphthyl (26)

An oven-dried 20 mL round-bottom flask was charged with bromide fromExample 14 (300 mg, 0.8 mmol) and THF (8 mL). The mixture was purgedwith argon and cooled to −78° C., then n-butyllithium (0.6 mL, 0.9 mmol)was added dropwise. The solution and stirred at −78° C. for 45 min, thenchlorodiphenylphosphine (229 mg, 1.0 mmol) was added dropwise. Thereaction was stirred for 1 hour at −78° C., then was allowed to warn toroom temperature and stirred for 18 hours. Saturated aqueous ammoniumchloride (2 mL) was added and the reaction mixture was extracted withether (2×10 mL). The combined organic extracts were dried over anhdrousmagnesium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified by flash chromatography on silica gel to give 340mg (88%) of 26 as colorless crystals.

Example 16 Synthesis of2-N,N-dimethylamino-2′-dicyclohexylphoshino-1,1′-binaphthyl (27)

An oven-dried 20 mL round-bottom flask was charged with bromide fromExample 14 (600 mg, 1.6 mmol) and THF (16 mL). The mixture was purgedwith argon and cooled to −78° C., then n-butyllithium (1.1 mL, 1.8 mmol)was added dropwise. The solution was stirred at −78° C. for 45 min, thenchlorodicyclohexylphosphine (484 mg, 2.1 mmol) was added dropwise. Thereaction was stirred for 1 hour at −78° C., then was allowed to warm toroom temperature and stirred for 18 hours. Saturated aqueous ammoniumchloride (2 mL) was added and the reaction mixture was extracted withether (2×10 mL). The combined organic extracts were dried over anhdrousmagnesium sulfate, filtered, and concentrated in vacuo. The crudematerial was recrystalized from dichloromethane and methanol to give 623mg (79%) of 27 as colorless crystals.

Example 17 Synthesis of N-(4-methoxyphenyl)pyrrolidine

An oven dried test tube was charged with Pd₂(dba)₃ (4.5 mg, 0.005 mmol),27 (7.4 mg, 0.015 mmol), 4-chloroanisole (140 mg, 0.98 mmol),pyrrolidine (85 mg, 1.2 mmol), NaOt-Bu (135 mg, 1.4 mmol), toluene (2mL), and purged with argon. The mixture was heated to 80° C. and stirredfor 18 hours. The reaction mixture was cooled to room temperature,diluted with ether (5 mL), filtered through a plug of celite, andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel to give 165 mg (95%) of the title product as colorlesscrystals.

Example 18 Synthesis of N-benzyl-p-toluidine

An oven dried resealable Schlenk tube was purged with argon and chargedwith Pd₂(dba)₃ (4.6 mg, 0.005 mmol, 1.0 mol % Pd), 27 (7.4 mg, 0.015mmol, 1.5 mol %), and NaOtBu (135 mg, 1.4 mmol). The tube was purgedwith argon and toluene (2 mL), 4-chlorotoluene (0.12 mL, 1.0 mmol), andbenzylamine (0.165 mL, 1.5 mmol) were added through a rubber septum. Theseptum was replaced with a teflon screw cap, the tube was sealed, andthe mixture was heated to 100° C. with stirring until the starting arylchloride had been completely consumed as judged by GC analysis. A smallamount of diarylated benzylamine was detected in the crude reactionmixture (GC ratio of product/diarylated benzylamine=16/1). The reactionmixture was cooled to room temperature, diluted with ether (20 mL), andextracted with 1 M HCl (5×40 mL). The organic phase was discarded andthe combined aqueous extracts were basisified to pH 14 with 6M NaOH andextracted with ether (4×50 mL). The combined organic extracts were driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo togive give 175 mg (89%) of a pale yellow oil.

Example 19 Synthesis of N-(4-methylphenyl)indole

An oven-dried resealable Schlenk tube was purged with argon and chargedwith Pd₂(dba)₃ (11.2 mg, 0.012 mmol, 2.5 mol % Pd), 2 [Example 1] (14.4mg, 0.036 mmol, 7.5 mol %), NaOt-Bu (130 mg, 1.35 mmol) and indole (115mg, 0.98 mmol). The tube was purged with argon then toluene (1.0 mL) and4-bromotoluene (120 μL, 0.98 mmol) were added through a rubber septum.The septum was removed, the tube was sealed with a teflon screw cap andthe mixture was stirred at 100° C. for 21 h. The reaction was thendiluted with ether (20 mL), filtered through celite and concentrated invacuo. The crude material was purified by flash chromatography on silicagel to afford 191 mg (94%) of a colorless oil.

Example 20 Synthesis of N-(4-fluorophenyl)indole

An oven-dried resealable Schlenk tube was purged with argon and chargedwith Pd₂(dba)₃ (11.5 mg, 0.013 mmol, 5 mol % Pd), 2 [Example 1] (14.8mg, 0.038 mmol, 7.5 mol %), NaOt-Bu (68 mg, 0.71 mmol) and indole (60mg, 0.51 mmol). The tube was purged with argon then toluene (0.5 mL) and1-bromo-4-fluorobenzene (55 μL, 0.50 mmol) were added through a rubberseptum. The septum was removed, the tube was sealed with a teflon screwcap and the mixture was stirred at 100° C. for 36 h. The reaction wasthen diluted with ether (20 mL), filtered through celite andconcentrated in vacuo. The crude material was purified by flashchromatography on silica gel to afford 81 mg (77%) of a colorless oil.

Example 21 Synthesis of N-(4-methylphenyl)indole

An oven-dried resealable Schlenk tube was purged with argon and chargedwith Pd₂(dba)₃ (11.6 mg, 0.012 mmol, 5 mol % Pd), 2 [Example 1] (11.0mg, 0.028 mmol, 5.5 mol %), Cs₂CO₃ (230 mg, 0.75 mmol) and indole (60mg, 0.51 mmol). The tube was purged with argon then toluene (1.0 mL) and4-chlorotoluene (60 μL, 0.51 mmol) were added through a rubber septum.The septum was removed, the tube was sealed with a teflon screw cap andthe mixture was stirred at 100° C. for 24 h. The reaction was thendiluted with ether (20 mL), filtered through celite and concentrated invacuo. The crude material was purified by flash chromatography on silicagel to afford 94 mg (89%) of a colorless oil.

Example 22 Synthesis of 2-Bromo-2′-methoxy-1,1′-biphenyl

2-Bromoiodobenzene (640 μL, 5.0 mmol) was added to a suspension ofPd(PPh₃)₄ (305 mg, 0.26 mmol) in DME (100 mL) at room temperature underargon. After 15 min at room temperature, a solution of2-methoxyphenylboronic acid (760 mg, 5.0 mmol) in ethanol (2 mL) wasadded, followed by aqueous Na₂CO₃ (2.0 M, 5 mL, 10 mmol). The reactionvessel was fitted with a reflux condenser and heated to reflux underargon for 22.5 h. The reaction mixture was then cooled to roomtemperature and filtered through Celite. The filter cake was washed withether and water, and the filtrate was concentrated in vacuo. Theresulting aqueous residue was diluted with brine and extracted withether. The ethereal layer was dried (MgSO₄), filtered and concentrated.The crude residue was purified by flash chromatography on silica gel toafford 823 mg (63%) of a colorless oil.

Example 23 Synthesis of 2-Dicyclohexylphosphino-2′-methoxy-1,1′-biphenyl

A solution of 1 (535 mg, 2.03 mmol) in THF (20 mL) was cooled to −78° C.under argon, then n-BuLi (1.6 M in hexane, 1.35 mL, 2.16 mmol) was addeddropwise. After 2.5 h at −78° C., a solution ofchlorodicyclohexylphosphine (570 mg, 2.45 mmol) in THF (3 mL) was addedover 10 min. The reaction mixture was then allowed to warm to roomtemperature overnight, then quenched with saturated aqueous NaHCO₃ andconcentrated in vacuo. The resulting aqueous suspension was extractedwith ether (2×50 mL), and the combined ethereal layers were dried(Na₂SO₄), filtered and concentrated in vacuo. The resulting crude solidwas recrystallized from ethanol to afford 420 mg (54%) of a white solid.

Example 24 Synthesis of N-(4-methylphenyl)indole

An oven-dried test tube was purged with argon and then charged with2-dicyclohexylphosphino-2′-methoxy-1,1′-biphenyl (14.5 mg, 0.038 mmol,7.5 mol %) and Pd₂(dba)₃ (11.6 mg, 0.013 mmol, 5.0 mol % Pd). Toluene(1.0 mL), indole (71 mg, 0.61 mmol), 4-chlorotoluene (60 mL, 0.51 mmol),and NaOt-Bu (70 mg, 0.73 mmol) were then added. The tube was fitted witha septum, purged with argon and heated at 100° C. for 28 h. The reactionwas then cooled to room temperature, diluted with ether (20 mL),filtered through Celite and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel to afford 99 mg (94%) ofa colorless oil.

Example 25 Synthesis of 2-(di-tert-butylphosphino)biphenyl

A solution of 2-bromobiphenyl (5.38 g, 23.1 mmol) and a few iodinecrystals in 40 mL of THF with magnesium turnings (617 mg, 25.4 mmol) washeated to a reflux for 2 h. Heat was temporarily removed for theaddition of cuprous chloride (2.40 g, 24.2 mmol) followed bychlorodi-tert-butylphosphine. Heating was resumed for 8 h. The reactionmixture was then removed from heat and allowed to cool to rt. Thereaction mixture was poured onto 200 mL of 1:1 hexane/ether. Thesuspension was filtered and the filtercake was washed with 60 mL ofhexane. The solid was partitioned between 150 mL of 1:1 hexane/ethylacetate and 60 mL of concentrated ammonium hydroxide with 100 mL ofwater. The organic layer was washed with 100 mL of brine, dried overanhydrous sodium sulfate, and concentrated in vacuo. The white solid wasrecrystallized from 30 mL of MeOH to give white crystals of2-(di-tert-butylphosphino)biphenyl (4.01 g, 58%). A second crop (464 mg,67%) was obtained by recrystallization from 50 mL of MeOH and 25 mL ofwater.

Example 26 General Procedure for Determining the Effect of VariousAdditives on the Preparation of 4-methylbiphenyl Via Suzuki Coupling

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (4.5 mg, 0.015 mmol, 1.5 mol %),phenylboron dihydroxide (183 mg, 1.5 mmol), additive (3.0 mmol), and4-chlorotoluene (0.12 mL, 1.0 mmol). The tube was evacuated andbackfilled with argon, and THF (2 mL) was added through a rubber septum.The reaction mixture was stirred at room temperature for 20 hours. Thereaction mixture was then diluted with ethyl acetate (30 mL) and pouredinto a separatory funnel. The mixture was washed with 2.0M NaOH (20 mL),followed by brine (20 mL). The organic layer was submitted for GCanalysis giving the results tabulated below.

Additive Conversion Cesium Fluoride 55% Potassium Fluoride 62% PotassiumCarbonate 10% Potassium Phosphate 38% Sodium Acetate  0%

Example 27 Synthesis of 4-t-butylbiphenyl using K₃PO₄ as base with 0.1mol % Pd

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with phenylboron dihydroxide (183 mg, 1.5 mmol), andpotassium phosphate (425 mg, 2.0 mmol). The tube was evacuated andbackfilled with argon, and DME (1.5 mL) and 1-bromo-4-t-butylbenzene(0.17 mL, 1.0 mmol) were added through a rubber septum. A separate flaskwas charged with Pd₂(dba)₃ (4.6 mg, 0.005 mmol),2-(di-tert-butylphosphino)biphenyl (4.5 mmol, 0.015 mmol), and DME (1mL). The mixture was stirred for 1 minute at room temperature, then 100μL of this solution (0.1 mol % Pd, 0.15 mol %2-(di-tert-butylphosphino)biphenyl) was added to the Schlenk tubefollowed by additional THF (1.5 mL). The septum was removed, the tubewas sealed with a teflon screw cap and the mixture was stirred at roomtemperature for 2 minutes, then heated to 80° C. with stirring until thestarting aryl bromide had been completely consumed as judged by GCanalysis. The reaction mixture was then diluted with ether (20 mL) andpoured into a separatory funnel. The mixture was washed with 1M NaOH (20mL), and the layers were separated. The aqueous layer was extracted withether (20 mL), and the combined organic extracts were dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo. Thecrude material was then purified by flash chromatography on silica gelto give 199 mg (95%) of a glassy solid.

Example 28 Synthesis of 4-t-butylbiphenyl using CsF as base with 0.05mol % Pd

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with phenylboron dihydroxide (183 mg, 1.5 mmol), andcesium fluoride (456 mg, 3.0 mmol). The tube was evacuated andbackfilled with argon, and THF (1.5 mL) and 1-bromo-4-t-butylbenzene(0.17 mL, 1.0 mmol) were added through a rubber septum. A separate flaskwas charged with Pd₂(dba)₃ (4.6 mg, 0.005 mmol),2-(di-tert-butylphosphino)biphenyl (4.5 mmol, 0.015 mmol), and THF (1mL). The mixture was stirred for 1 minute at room temperature, then 50μL of this solution (0.05 mol % Pd, 0.075 mol %2-(di-tert-butylphosphino)biphenyl) was added to the Schlenk tubefollowed by additional THF (1.5 mL). The septum was removed, the tubewas sealed with a teflon screw cap and the mixture was stirred at roomtemperature for 2 minutes, then heated to 80° C. with stirring until thestarting aryl bromide had been completely consumed as judged by GCanalysis. The reaction mixture was then diluted with ether (20 mL) andpoured into a separatory funnel. The mixture was washed with 1M NaOH (20mL), and the layers were separated. The aqueous layer was extracted withether (20 mL), and the combined organic extracts were dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo. Thecrude material was then purified by flash chromatography on silica gelto give 202 mg (96%) of a glassy solid.

Example 29 Optimized Synthesis of 4-methylbiphenyl Utilizing KF

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),phenylboron dihydroxide (183 mg, 1.5 mmol), and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF(1 mL) and 4-chlorotoluene (0.12 mL, 1.0 mmol) were added through arubber septum. The tube was sealed with a teflon screwcap, and thereaction mixture was stirred at room temperature until the starting arylchloride had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL) and poured into aseparatory funnel. The mixture was washed with 1.0 M NaOH (20 mL), andthe aqueous layer was extracted with ether (20 mL). The combined organiclayers were washed with brine (20 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated. The crude material was purified byflash chromatography on silica gel to afford 158 mg (94%) of the titlecompound.

Example 30 Synthesis of 2-cyanomethylbiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),phenylboron dihydroxide (183 mg, 1.5 mmol), and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF(1 mL) and 2-chlorobenzyl cyanide (152 mg, 1.0 mmol) were added througha rubber septum. The tube was sealed with a teflon screwcap, and thereaction mixture was stirred at room temperature until the starting arylchloride had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL) and poured into aseparatory funnel. The mixture was washed with 1.0 M NaOH (20 mL), andthe aqueous layer was extracted with ether (20 mL). The combined organiclayers were washed with brine (20 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated. The crude material was purified byflash chromatography on silica gel to afford 178 mg (92%) of the titlecompound.

Example 31 Synthesis of 4-carbomethoxy-3′-acetylbiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),3-acetylphenyl boronic acid (246 mg, 1.5 mmol), potassium fluoride (174mg, 3.0 mmol), and methyl-4-chlorobenzoate (171 mg, 1.0 mmol). The tubewas evacuated and backfilled with argon, and THF (1 mL) was addedthrough a rubber septum. The tube was sealed with a teflon screwcap, andthe reaction mixture was stirred at room temperature until the startingaryl chloride had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL) and poured into aseparatory funnel. The mixture was washed with water (20 mL), and theaqueous layer was extracted with ether (20 mL). The combined organiclayers were washed with brine (20 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated. The crude material was purified byflash chromatography on silica gel to afford 229 mg (90%) of the titlecompound.

Example 32 Synthesis of 4-cyanobiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0mmol), and 4-chlorobenzonitrile (136 mg, 1.0 mmol). The tube wasevacuated and backfilled with argon, and THF (1 mL) was added through arubber septum. The tube was sealed with a teflon screwcap, and thereaction mixture was stirred at room temperature until the starting arylchloride had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL) and poured into aseparatory funnel. The mixture was washed with water (20 mL), and theaqueous layer was extracted with ether (20 mL). The combined organiclayers were washed with brine (20 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated. The crude material was purified byflash chromatography on silica gel to afford 159 mg (89%) of the titlecompound.

Example 33 Synthesis of 4-formyl-4′-ethoxybiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (1.1 mg, 0.005 mmol, 0.5 mol%), 2-(di-tert-butylphosphino)biphenyl (3.0 mg, 0.01 mmol, 1.0 mol %),4-ethoxyphenylboronic acid (249 mg, 1.5 mmol), potassium fluoride (174mg, 3.0 mmol), and 4-bromobenzaldehyde (185 mg, 1.0 mmol). The tube wasevacuated and backfilled with argon, and THF (1 mL) was added through arubber septum. The tube was sealed with a teflon screwcap, and thereaction mixture was stirred at room temperature until the starting arylbromide had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL) and poured into aseparatory funnel. The mixture was washed with water (20 mL), and theaqueous layer was extracted with ether (20 mL). The combined organiclayers were washed with brine (20 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated. The crude material was purified byflash chromatography on silica gel to afford 203 mg (90%) of the titlecompound.

Example 34 Synthesis of 4-hydroxybiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %),phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0mmol), and 4-bromophenol (173 mg, 1.0 mmol). The tube was evacuated andbackfilled with argon, and THF (1 mL) was added through a rubber septum.The tube was sealed with a teflon screwcap, and the reaction mixture wasstirred at room temperature until the starting aryl bromide had beencompletely consumed as judged by GC analysis. The reaction mixture wasthen diluted with ether (30 mL), filtered through celite, andconcentrated. The crude material was purified by flash chromatography onsilica gel to afford 154 mg (91%) of the title compound.

Example 35 Synthesis of 2-hydroxymethylbiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %),phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0mmol), and 2-bromobenzyl alcohol (187 mg, 1.0 mmol). The tube wasevacuated and backfilled with argon, and THF (1 mL) was added through arubber septum. The tube was sealed with a teflon screwcap, and thereaction mixture was stirred at room temperature until the starting arylbromide had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL), filtered througthcelite, and concentrated. The crude material was purified by flashchromatography on silica gel to afford 153 mg (83%) of the titlecompound.

Example 36 Synthesis of 2,5-dimethylbiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),phenylboronic acid (183 mg, 1.5 mmol), and potassium fluoride (174 mg,3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1mL) and 2-bromo-p-xylene (0.138 mL, 1.0 mmol) were added through arubber septum. The tube was sealed with a teflon screwcap, and thereaction mixture was stirred at room temperature until the starting arylbromide had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL), filtered throughcelite, and concentrated. The crude material was purified by flashchromatography on silica gel to afford 149 mg (82%) of the titlecompound.

Example 37 Synthesis of 4-methoxybiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),phenylboronic acid (183 mg, 1.5 mmol), and potassium fluoride (174 mg,3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1mL) and 4-chloroanisole (0.123 mL, 1.0 mmol) were added through a rubberseptum. The tube was sealed with a teflon screwcap, and the reactionmixture was stirred at room temperature until the starting aryl chloridehad been completely consumed as judged by GC analysis. The reactionmixture was then diluted with ether (30 mL), filtered through celite,and concentrated. The crude material was purified by flashchromatography on silica gel to afford 176 mg (96%) of the titlecompound.

Example 38 Synthesis of N-acetyl-4-aminobiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %),phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0mmol), and 4′-bromoacetanilide (214 mg, 1.0 mmol). The tube wasevacuated and backfilled with argon, and THF (1 mL) was added through arubber septum. The tube was sealed with a teflon screwcap, and thereaction mixture was stirred at room temperature until the starting arylbromide had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL), filtered throughcelite, and concentrated. The crude material was purified by flashchromatography on silica gel to afford 182 mg (86%) of the titlecompound.

Example 39 Synthesis of 4-nitrobiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol, 2.0 mol %),phenylboronic acid (183 mg, 1.5 mmol), potassium fluoride (174 mg, 3.0mmol), and 1-chloro-4-nitrobenzene (158 mg, 1.0 mmol). The tube wasevacuated and backfilled with argon, and THF (1 mL) was added through arubber septum. The tube was sealed with a teflon screwcap, and thereaction mixture was stirred at room temperature until the starting arylchloride had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL), filtered throughcelite, and concentrated. The crude material was purified by flashchromatography on silica gel to afford 196 mg (98%) of the titlecompound.

Example 40 Synthesis of 2,6-dimethylbiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),phenylboronic acid (183 mg, 1.5 mmol), and potassium fluoride (174 mg,3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1mL) and 2-bromo-m-xylene (0.144 mL, 1.0 mmol) were added through arubber septum. The tube was sealed with a teflon screwcap, and thereaction mixture was stirred at 65° C. until the starting aryl bromidehad been completely consumed as judged by GC analysis. The reactionmixture was then diluted with ether (30 mL), filtered through celite,and concentrated. The crude material was purified by flashchromatography on silica gel to afford 144 mg (79%) of the titlecompound.

Example 41 Synthesis of 2-methoxy-4′-methylbiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),2-methoxyphenylboronic acid (228 mg, 1.5 mmol), and potassium fluoride(174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon,and THF (1 mL) and 4-chlorotoluene (0.144 mL, 1.0 mmol) were addedthrough a rubber septum. The tube was sealed with a teflon screwcap, andthe reaction mixture was stirred at 65° C. until the starting arylchloride had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (30 mL), filtered throughcelite, and concentrated. The crude material was purified by flashchromatography on silica gel to afford 188 mg (95%) of the titlecompound.

Example 42 Synthesis of 2-methoxy-2′-acetylbiphenyl

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),2-methoxyphenylboronic acid (228 mg, 1.5 mmol), and potassium phosphate(425 mg, 2.0 mmol). The tube was evacuated and backfilled with argon,and toluene (3 mL) and 2′-chloroacetophenone (0.13 mL, 1.0 mmol) wereadded through a rubber septum. The tube was sealed with a teflonscrewcap, and the reaction mixture was heated to 65° C. with stirringuntil the starting aryl chloride had been completely consumed as judgedby GC analysis. The reaction mixture was then diluted with ether (30 mL)and poured into a separatory funnel. The mixture was washed with water(20 mL), and the aqueous layer was extracted with ether (20 mL). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated. The crudematerial was purified by flash chromatography on silica gel to afford201 mg (89%) of the title compound.

Example 43 Synthesis of 3-(3-acetylphenyl)pyridine

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),3-acetylphenylboronic acid (246 mg, 1.5 mmol), and potassium fluoride(173 mg, 3.0 mmol). The tube was evacuated and backfilled with argon,and THF (1 mL) and 3-chloropyridine (0.095 mL, 1.0 mmol) were addedthrough a rubber septum. The tube was sealed with a teflon screwcap, andthe reaction mixture was heated to 50° C. with stirring until thestarting aryl chloride had been completely consumed as judged by GCanalysis. The reaction mixture was then diluted with ether (30 mL) andpoured into a separatory funnel. The mixture was washed with water (20mL), and the aqueous layer was extracted with ether (20 mL). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated. The crudematerial was purified by flash chromatography on silica gel to afford181 mg (92%) of the title compound.

Example 44 Synthesis of 4-acetylbiphenyl from an aryl chloride utilizing0.02 mol % Pd

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with phenylboronic acid (228 mg, 1.5 mmol), andpotassium phosphate (425 mg, 2.0 mmol). The tube was evacuated andbackfilled with argon, and toluene (1.5 mL) and 4-chloroacetophenone(0.13 mL, 1.0 mmol) were added through a rubber septum. In a separateflask, palladium acetate (2.2 mg, 0.01 mmol) and2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.02 mmol) were dissolved in5 mL THF under argon. A portion of this solution (100 μL, 0.0002 mmolPd, 0.02 mol % Pd) was added to the reaction mixture, followed byadditional toluene (1.5 mL) through a rubber septum. The tube was sealedwith a teflon screwcap, and the reaction mixture was heated to 100° C.with stirring until the starting aryl chloride had been completelyconsumed as judged by GC analysis. The reaction mixture was then dilutedwith ether (30 mL) and poured into a separatory funnel. The mixture waswashed with water (20 mL), and the aqueous layer was extracted withether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered, and concentrated.The crude material was purified by flash chromatography on silica gel toafford 178 mg (91%) of the title compound.

Example 45 Synthesis of 4-acetylbiphenyl from an aryl bromoide utilizing0.000001 mol % Pd

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with phenylboronic acid (228 mg, 1.5 mmol), andpotassium phosphate (425 mg, 2.0 mmol), and 4-bromoacetophenone (199 mg,1.0 mmol). The tube was evacuated and backfilled with argon, and toluene(1.5 mL) was added through a rubber septum. In a separate flask in anitrogen filled glovebox, palladium acetate (4.5 mg, 0.02 mmol) and2-(di-tert-butylphosphino)biphenyl (12.0 mg, 0.04 mmol) were dissolvedin 20 mL THF under argon. A portion of this solution (10 μL, 0.00001mmol Pd, 0.001 mol % Pd) was added to a second flask contaninig 10 mLTHF). A portion of this second solution (10 μL, 0.00000001 mmol Pd,0.000001 mol % Pd) was added to the reaction mixture, followed byadditional toluene (1.5 mL) through a rubber septum. The tube was sealedwith a teflon screwcap, and the reaction mixture was heated to 100° C.with stirring until the starting aryl bromide had been completelyconsumed as judged by GC analysis. The reaction mixture was then dilutedwith ether (30 mL) and poured into a separatory funnel. The mixture waswashed with water (20 mL), and the aqueous layer was extracted withether (20 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered, and concentrated.The crude material was purified by flash chromatography on silica gel toafford 176 mg (90%) of the title compound.

Example 46 Optimized synthesis of 2-acetylbiphenyl utilizing potassiumfluoride

An oven dried Schlenk tube was evacuated and backfilled with argon andcharged with palladium acetate (4.5 mg, 0.02 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (11.9 mg, 0.040 mmol, 2.0 mol %),phenylboron dihydroxide (366 mg, 3.0 mmol), and potassium fluoride (349mg, 6.0 mmol). The tube was evacuated and backfilled with argon, and THF(2 mL) and 2-chloroacetophenone (0.26 mL, 2.0 mmol) were added through arubber septum. The reaction mixture was stirred at room temperatureuntil the starting aryl chloride had been completely consumed as judgedby GC analysis. The reaction mixture was then diluted with ethyl acetate(30 mL) and poured into a separatory funnel. The mixture was washed with2.0M NaOH (20 mL). The organic layer was washed with brine (20 mL),dried over anhydrous sodium sulfate, filtered, and concentrated. Thecrude material was purified by flash chromatography on silica gel toafford 369 mg (94%) of the title compound.

Example 47 Optimized synthesis of 2-formyl-4′-diphenylketiminebiphenylutilizing potassium fluoride

An oven dried Schlenk tube was evacuated and backfilled with argon andcharged with palladium acetate (4.5 mg, 0.02 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (11.9 mg, 0.040 mmol, 2.0 mol %),4-diphenylketiminephenyl bromide (672 mg, 2.0 mmol), 2-formylphenylborondihydroxide (450 mg, 3.0 mmol), and potassium fluoride (349 mg, 6.0mmol). The tube was evacuated and backfilled with argon, and THF (2 mL)was added through a rubber septum. The reaction mixture was stirred atroom temperature until the starting aryl bromide had been completelyconsumed as judged by GC analysis. The reaction mixture was then dilutedwith ethyl acetate (30 mL) and poured into a separatory funnel. Themixture was washed with 2.0M NaOH (20 mL). The organic layer was washedwith brine (20 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was purified by flash chromatography onsilica gel to afford 647 mg (90%) of the title compound.

Example 48 Synthesis of 3-acetyl-3′,5′-dimethoxybiphenyl

An oven dried Schlenk tube was evacuated and backfilled with argon andcharged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),3,5-dimethoxyphenyl chloride (173 mg, 1.0 mmol), 3-acetylphenylborondihydroxide (246 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0mmol). The tube was evacuated and backfilled with argon, and THF (1 mL)was added through a rubber septum. The reaction mixture was stirred atroom temperature until the starting aryl chloride had been completelyconsumed as judged by GC analysis. The reaction mixture was then dilutedwith ethyl acetate (30 mL) and poured into a separatory funnel. Themixture was washed with 2.0 M NaOH (20 mL). The organic layer was washedwith brine (20 mL), dried over anhydrous magnesium sulfate, filtered,and concentrated. The crude material was purified by flashchromatography on silica gel to afford 232 mg (91%) of the titlecompound.

Example 49 Synthesis of 2-phenylthiophene

An oven dried Schlenk tube was evacuated and backfilled with argon andcharged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %),2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %),phenylboron dihydroxide (183 mg, 1.5 mmol), and potassium fluoride (174mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF(1 mL) and 2-bromothiophene (0.097 mL, 1.0 mmol) were added through arubber septum. The reaction mixture was stirred at room temperatureuntil the starting aryl bromide had been completely consumed as judgedby GC analysis. The reaction mixture was then diluted with ethyl acetate(30 mL) and poured into a separatory funnel. The mixture was washed with2.0M NaOH (20 mL). The organic layer was washed with brine (20 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated. Thecrude material was purified by flash chromatography on silica gel toafford 159 mg (99%) of the title compound.

Example 50 Room temperature synthesis of 4-methylbiphenyl utilizing theligand 2,6-dimethoxyphenyl-di-t-butylphosphine

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (4.4 mg, 0.01 mmol, 1 mol %),2,6-dimethoxyphenyl-di-t-butylphosphine (4.2 mg, 0.015 mmol, 1.5 mol %),phenylboron dihydroxide (183 mg, 1.5 mmol), and cesium fluoride (456 mg,3.0 mmol). The tube was evacuated and backfilled with argon, and THF (3mL) and 4-chlorotoluene (0.12 mL, 1.0 mmol) were added through a rubberseptum. The septum was removed, the tube was sealed with a teflon screwcap and the mixture was stirred at room temperature until the startingaryl chloride had been completely consumed as judged by GC analysis. Thereaction mixture was then diluted with ether (20 mL) and poured into aseparatory funnel. The mixture was washed with 1M NaOH (20 mL), and thelayers were separated. The aqueous layer was extracted with ether (20mL), and the combined organic extracts were dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The crudematerial was then purified by flash chromatography on silica gel to give164 mg (98%) of a glassy solid.

Example 51 Room temperature synthesis of 4-methylbiphenyl utilizing theligand 2,4,6-trimethoxyphenyl-di-t-butylphosphine

An oven dried resealable Schlenk tube was evacuated and backfilled withargon and charged with palladium acetate (4.4 mg, 0.01 mmol, 1 mol %),2,4,6-trimethoxyphenyl-di-t-butylphosphine (4.7 mg, 0.015 mmol, 1.5 mol%), phenylboron dihydroxide (183 mg, 1.5 mmol), and cesium fluoride (456mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF(3 mL) and 4-chlorotoluene (0.12 mL, 1.0 mmol) were added through arubber septum. The septum was removed, the tube was sealed with a teflonscrew cap and the mixture was stirred at room temperature until thestarting aryl chloride had been completely consumed as judged by GCanalysis. The reaction mixture was then diluted with ether (20 mL) andpoured into a separatory funnel. The mixture was washed with 1M NaOH (20mL), and the layers were separated. The aqueous layer was extracted withether (20 mL), and the combined organic extracts were dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo. Thecrude material was then purified by flash chromatography on silica gelto give 165 mg (98%) of a glassy solid.

Example 52 Synthesis of 4-(trifluoromethyl)phenylboronic acid

An oven dried Schlenk tube was charged with magnesium turnings (766 mg,31.5 mmol), evacuated, and backfilled with argon. To the reaction vesselwas added 10 mL of ether followed by 4-(trifluoromethyl)phenyl bromide(4.20 mL, 30.0 mmol). The reaction mixture was stirred without externalheating for 1 hour, during which time an exotherm occurred and thensubsided. The solution was diluted with ether (10 mL) and transferredvia cannula to a flask containing triisopropylborate (13.8 mL, 60.0mmol) in 1:1 THF/ether (20 mL) at −78° C. The resulting reaction mixturewas kept at −78° C. for 15 minutes and then was allowed to warm to roomtemperature. After stirring at room temperature for 15 minutes, thereaction mixture was poured onto 2.0 M HCl (60 mL). The mixture wastransferred to a separatory funnel, extracted with ethyl acetate (60mL), washed with water (60 mL), and brine (60 mL). The organic solutionwas dried over anhydrous sodium sulfate and concentrated in vacuo. Thecrude material was dissolved in 2:1 hexane/ethyl acetate (90 mL) andactivated charcoal was added. The mixture was filtered and the productcrystallized upon cooling. The crystals were collected by filtration toafford 1.98 g (35%) of pale yellow needles.

Example 53 Synthesis of 2-bromo-4′-(trifluoromethyl)biphenyl

An oven dried Schlenk tube was evacuated and backfilled with argon andcharged with tetrakis(triphenylphosphine)palladium (289 mg, 0.25 mmol,5.0 mol %), 2-bromoiodobenzene (0.83 mL, 6.50 mmol),4-(trifluoromethyl)phenylboronic acid (950 mg, 5.0 mmol), and sodiumcarbonate (2.86 g, 27.0 mmol). The tube was evacuated and backfilledwith argon. To the tube was added (degassed) dimethoxyethane (45 mL),ethanol (2 mL), and water (15 mL) through a rubber septum. The reactionmixture was heated to 85° C. with stirring for 32 hours. The reactionmixture was then diluted with 2:1 hexane/ethyl acetate (100 mL) andpoured into a separatory funnel. The mixture was washed with water (80mL), and brine (80 mL). The organic layer was dried over anhydroussodium sulfate, decanted, and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica gel to afford 1.01 g(67%) of the product.

Example 54 Synthesis of2-(di-t-butylphosphino)-4′-(trifluoromethyl)biphenyl

An oven dried Schlenk tube was evacuated and backfilled with argon andcharged with magnesium turnings (90 mg, 3.69 mmol),2-bromo-4′-(trifluoromethyl)biphenyl (1.01 g, 3.35 mmol), and a crystalof iodine. The tube was purged with argon for 5 minutes, then THF (6 mL)was added through a rubber septum and the reaction mixture was heated toreflux for 1 hour. The reaction mixture was cooled to room temperatureand cuprous chloride (365 mg, 3.69 mmol) and chloro-di-t-butylphosphine(0.765 mL, 4.03 mmol) were added. Heating was resumed for 14 hours. Thereaction mixture was then cooled to room temperature and diluted withether (40 mL). The suspension was filtered to isolate the solid. Thesolid was partitioned between ethyl acetate (60 mL) and 38% ammoniumhydroxide (75 mL). The aqueous layer was extracted with ethyl acetate(60 mL). The combined organic layers were washed with brine (50 mL),dried over anhydrous sodium sulfate, decanted, and concentrated invacuo. The product was crystallized from MeOH (10 mL) to afford 131 mg(11%) of pale yellow needles. A second crop was isolated byconcentrating the mother liquor and recrystallizing the solid from MeOH(20 mL) and water (2 mL) to afford 260 mg (21%) of the product.

Example 55 Synthesis of 2-(di-1-adamantylphosphino)biphenyl

An oven-dried, round-bottom flask was charged with magnesium turnings(15.3 g, 0.63 mol) and 1-bromoadamantane (9.0 g, 0.041 mol). The flaskwas evacuated and backfilled with argon two times. To the reactionvessel 45 mL ether was added and the mixture was gently refluxed for 15hours, without mechanical stirring. The resulting solution of Grignardreagent was taken up in a syringe, and added very slowly dropwise to aseparate flame-dried, two-necked, round-bottom flask equipped with areflux condenser which had been charged with PCl₃ (0.9 mL, 10 mmol) and15 mL ether which had been cooled to −40° C. During the addition thetemperature was monitored and kept below −25° C. The resulting mixturewas stirred for 30 minutes at −45° C., then the cooling bath was removedand the reaction mixture was allowed to warm slowly to room temperature.After stirring for an additional 30 minutes at room temperature, thereaction vessel was placed into a heated oilbath (37° C.) and was gentlyrefluxed for 22 hours. The mixture was cooled to room temperature, andthe solution was filtered through a cannula filter. The solvent as wellas some of the adamantane byproduct was removed in vacuo, withoutexposing the product to air to afford crudedi-1-adamantylchlorophosphine.

An oven dried Schlenk tube was charged with magnesium turnings (240 mg,9.89 mmol), 2-bromo-biphenyl (1.55 mL, 7.5 mmol). The tube was evacuatedand backfilled with argon two times. To the above mixture THF (15 mL)was added through a rubber septum and the reaction mixture was heated toa mild reflux for 3 hours. The reaction mixture was then temporarilycooled to room temperature for the addition of cuprous chloride (930 mg,9.45 mmol) followed by a solution of the di-1-adamantylchlorophosphinein 5 mL THF. Heating was resumed for an additional 3 hours. The reactionmixture was cooled to room temperature, and ether (50 mL) and pentane(50 mL) were added. The resulting suspension was stirred for 10 minutes,during which time a heavy dark-brown precipitate formed. The suspensionwas filtered and the solid was collected on a fritted funnel. The solidwas partitioned between ethyl acetate-ether (100 mL 1:1) and 38%ammonium hydroxide-water (100 mL 1:1). The mixture was vigorously shakenseveral times over 30 minutes. The aqueos layer washed twice withether-ethyl acetate (1:1, 100 mL). The combined organic layers werewashed with brine (2×50 mL), dried over anhydrous magnesium sulfate,decanted, and concentrated in vacuo. The product was crystallized fromtoluene/methanol to afford 450 mg (5.8%) product as a white solid.

Example 56 Synthesis of 2-(di-t-butylphosphino)-2′-(isopropyl)biphenyl

A flame-dried Schlenk tube was evacuated and backfilled with argon twotimes, and was charged with 2-(bromo)-2′-(isopropyl)biphenyl (1.5 g,5.45 mmol) and ether (15 mL). The reaction mixture was cooled to −78°C., and t-BuLi (6.7 mL, 1.7 M in penate) was added dropwize via asyringe, through a rubber septum. After the addition was complete, thereaction mixture was stirred for an additional 15 minutes at −78° C. Thecooling bath was removed, and t-Bu₂PCl was added dropwise. Afterreaching room temperature, the reaction vessel was placed into a heatedoil bath (37° C.), and the reaction mixture was refluxed for 48 hours.The mixture was cooled to room temperature, a saturated solution ofaqueous ammonium chloride (10 mL) was added, and the resulting mixturewas partitioned between ether (100 mL) and water (50 mL). The organiclayer was dried over a 1:1 mixture of anhydrous magnesium sulfate andsodium sulfate, decanted and concentrated in vacuo. The product wascrystallized from MeOH to afford 601 mg (30%) of white needles.

Example 57 Synthesis of di-tbutyl-(o-cyclohexyl)phenyl phosphine (3)

An oven-dried Schlenk flask was allowed to cool to room temperatureunder an argon purge, and was charged with 1,2-dibromobenzene (1.2 mL,10.0 mmol), ether (20 mL), and THF (20 mL). The mixture was cooled to−119° C. with stirring using an ethanol/N₂ cold bath. n-butyllithium inhexanes (5.8 mL, 1.6 M, 9.3 mmol) was added slowly dropwise. The mixturewas stirred at −119° C. for 45 min, then cyclohexanone (0.98 mL, 9.5mmol) was added to the mixture. The mixture was stirred at −78° C. for30 min, then warmed to room temperature and stirred for 17 h. Themixture was quenched with saturated aqueous ammonium chloride (20 mL),diluted with ether (50 mL), and poured into a separatory funnel. Thelayers were separated and the aqueous phase was extracted with ether(1×20 mL). The organic layers were combined and washed with brine (20mL), dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo. The crude material was purified by flash chromatography onsilica gel to afford 1.91 g of 1 which was judged to be ˜86% pure by GCanalysis. This material was used without further purification.

A round bottomed flask was purged with argon and charged with alcohol 1(1.78 g, 7.0 mmol), dichloromethane (28 mL), triethylsilane (1.5 mL, 9.1mmol), and trifluoroacetic acid (1.1 mL, 14.7 mmol). The mixture wasstirred at room temperature for 1.5 h, then was quenched with solidpotassium carbonate (ca 2 g). The mixture was diluted with ether (50 mL)and transferred to a separatory funnel. The mixture was washed withsaturated aqueous NaHCO₃ (50 mL), and the organic phase was dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo toafford a mixture of 2 and 1-(2-bromophenyl)cyclohexene. The crudematerial was placed into a round bottomed flask, and the flask waspurged with argon. THF (2 mL) was added, and the mixture was cooled to0° C. with stirring. A solution of BH₃ in THF (7 mL, 1M, 7.0 mmol) wasadded dropwise to the mixture. The mixture was stirred at 0° C. for 1.5h, then warmed to room temperature and stirred for 19 h. Acetic acid (4mL) was added and the mixture was stirred at room temperature for 6 h.The mixture was then diluted with ether (50 mL) and poured into aseparatory funnel. The mixture was washed with 1M NaOH (50 mL), thelayers were separated, and the aqueous phase was extracted with ether(50 mL). The combined organic phases were washed with brine (50 mL),dried over anhydrous magnesium sulfate, filtered, and concentrated invacuo. The crude material was purified by flash chromatography on silicagel to afford 555 mg of 2 which was judged to be 93% pure by GCanalysis. This material was used without further purification.

An oven-dried Schlenk tube was cooled to room temperature under an argonpurge, and was charged with magnesium turnings (27 mg, 1.1 mmol), THF (1mL), and 1,2-dibromoethane (8 μL). The mixture was stirred at roomtemperature for 10 min, then 2 (239 mg, 1.0 mmol) was added in oneportion. The mixture was stirred at rt for 20 min, then heated to 60° C.for 15 min. The mixture was cooled to room temperature, the septum wasremoved from the flask, and copper (I) chloride (104 mg, 1.05 mmol) wasadded. The tube was capped with the septum and purged with argon for 1min. The tube was charged with di-t-butylchlorophosphine (0.23 mL, 1.2mmol) and additional THF (1 mL). The mixture was heated to 60° C. withstirring for 26 h. The mixture was cooled to room temperature andfiltered, and the solids were washed with ether/hexanes (50 mL, 1/1v/v). The organic solution was poured into a separatory funnel andwashed with ammonium hydroxide solution (3×50 mL), and brine (50 mL).The organic phase was then dried over anhydrous sodium sulfate,filtered, and concentrated. The crude material was purified by flashchromatography on silica gel to afford 3 as a white solid (141 mg),which was judged to be 92% pure by GC analysis. This material wasrecrystallized from hot methanol to afford 101 mg (˜3% overall from1,2-dibromobenzene) of 3 as a white, crystalline solid.

Example 58 Preparation of o-di-t-butylphosphino-o-terphenyl (3)

An oven-dried Schlenk tube was cooled to room temperature under an argonpurge, and was charged with magnesium turnings (243 mg, 11.0 mmol),ether (7 mL), and 1,2-dibromoethane (38 μL). The mixture was stirred atroom temperature until the evolution of gases ceased, then a solution of2-bromobiphenyl (1.7 mL, 10.0 mmol) in 5 mL ether was added dropwise.The mixture was stirred at room temperature for 1.75 h. The solution wasthen transferred to a separate flask containing a solution oftriisopropyl borate (4.6 mL, 20.0 mmol) in THF (20 mL) which had beencooled to 0° C. The mixture was stirred at 0° C. for 15 min, then warmedto room temperature and stirred for 21 h. The reaction was quenched with1M HCl (40 mL) and stirred at room temperature for 10 min. The solutionwas basisified to pH 14 with 6M NaOH, then extracted with ether (1×10mL). The organic phase was discarded and the aqueous phase was acidifiedto pH 2 with 6M HCl. The aqueous phase was extracted with ether (3×50mL), and the combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo. The crude material wasrecrystallized from ether/pentane at −20° C. to afford 1.0 g (51%) of 1as a white, crystalline solid.

An oven-dried Schlenk flask was cooled to room temperature under anargon purge, and was charged with tetrakis(triphenylphosphine)palladium(289 mg, 0.25 mmol, 5 mol %) sodium carbonate (2.86 g, 27 mmol), and 1(1.0 g, 5.0 mmol). The flask was purged with argon and DME (50 mL),ethanol (2 mL), water (15 mL), and 2-bromoiodobenzene (0.83 mL, 6.05mmol) were added through a rubber septem. The mixture was heated to 85°C. with stirring for 3 days. The mixture was cooled to room temperature,diluted with ether (100 mL), and poured into a separatory funnel. Thelayers were separated and the organic phase was washed with 1M NaOH(2×50 mL), washed with brine, dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo. The crude material was purified byflash chromatography on silica gel to afford 1.23 g (79%) of 2 as acolorless oil.

An oven-dried Schlenk tube was cooled to room temperature under an argonpurge, and was charged with magnesium turnings (54 mg, 2.2 mmol), THF (2mL), and 1,2-dibromoethane (9 μL). The mixture was stirred at roomtemperature for 15 min, then a solution of 2 (618 mg, 2.0 mmol) in 1 mLTHF was added dropwise. The mixture was stirred at rt for 1 h, then theseptum was removed from the flask, and copper (I) chloride (283 mg, 2.1mmol) was added. The tube was capped with the septum and purged withargon for 1 min. The tube was charged with di-t-butylchlorophosphine(0.46 mL, 2.4 mmol) and additional THF (1 mL). The mixture was heated to60° C. with stirring for 26 h. The mixture was cooled to roomtemperature and filtered, and the solids were washed with ether/hexanes(50 mL, 1/1 v/v). The organic solution was poured into a separatoryfunnel and washed with ammonium hydroxide solution (3×50 mL), and brine(50 mL). The organic phase was then dried over anhydrous sodium sulfate,filtered, and concentrated. The crude material was recrystallized fromhot methanol to afford 191 mg (26%) of 3 as a white, crystalline solid.

Example 59 Pd-Catalyzed Carbon-Nitrogen Bond Formation in tert-ButanolUsing (2′,4′,6′-triisopropylbiphenyl)dicyclohexylphosphine as Ligand

(2′,4′,6′-tri-isopropylbiphenyl)dicyclohexylphosphine (“Ligand 1”)

4-(4-Butyl-phenylamino)-benzamide

An oven-dried resealable Schlenk flask was evacuated and backfilled withargon. The flask was charged with Pd₂(dba)₃ (4.6 mg, 0.005 mmol, 1 mol %Pd), Ligand 1 (9.4 mg, 0.02 mmol, 2 mol %), ground K₂CO₃ (193 mg, 1.4mmol), and 4-amino-benzamide (163 mg, 1.2 mmol). The flask was evacuatedand backfilled with argon (3×) and then capped with a rubber septum. Tothe flask was added t-BuOH (1.5 mL), 4-n-butyl-chlorobenzene (168 mg,1.0 mmol) and t-BuOH (0.5 mL). The septum was replaced with a Teflonscrewcap, the flask was sealed, and the mixture was heated to 110° C.with stirring until the starting aryl chloride was consumed by GCanalysis (19 h). The reaction was cooled to room temperature, dilutedwith ethyl acetate, filtered through Celite, and concentrated underreduced pressure. The crude material was purified by columnchromatography on silica gel (eluting with EtOAc/hexanes, 8:2) to givethe desired product as a white solid (235 mg, 88%).

The same procedure using KOH (1.4 mmol, 78 mg) in place of potassiumcarbonate gave an 85% yield of the product.

3-(Methyl-phenyl-amino)-benzoic acid

An oven-dried resealable Schlenk flask was evacuated and backfilled withargon. The flask was charged with Pd₂ dba₃ (9.2 mg, 0.01 mmol, 2 mol %Pd), Ligand 1 (19 mg, 0.04 mmol, 4 mol %), pulverized KOH (168 mg, 3.0mmol), and 3-chlorobenzoic acid (156 mg, 1.0 mmol). The flask wasevacuated and backfilled with argon (3×) and then capped with a rubberseptum. To the flask was added t-BuOH (2.0 mL), N-methyl-aniline (0.163mL, 1.5 mmol) and t-BuOH (0.5 mL). The septum was replaced with a Teflonscrewcap, the flask was sealed, and the mixture was heated to 100° C.with stirring until the starting aryl chloride was consumed by GCanalysis (3 h, GC monitoring was conducted by diluting a small aliquotfrom the reaction with MeOH (1-2 mL), adding 2-3 drops H₂SO₄ and heatinguntil 0.5 mL liquid was left, filtering through a small pipette silicaplug and observing the disappearance of the corresponding methyl ester).The reaction was cooled to room temperature, diluted with 5% aq. NaOHand extracted with Et₂O. The aqueous layer was cooled to 0° C. andacidified with HCl (12.0 M) until pH ˜4. The aqueous layer was extractedwith Et₂O, dried over anh. MgSO₄, filtered, and concentrated underreduced pressure to give crude product (233 mg). The product waspurified by recrystallizing in hot hexanes/chloroform (5:1) to give alight yellow solid (191 mg, 84%, ≧95% pure).

4-(4-Butyl-phenylamino)-benzoic acid

An oven-dried resealable Schlenk flask was evacuated and backfilled withargon. The flask was charged with Pd₂ dba₃ (9.2 mg, 0.01 mmol, 2 mol %Pd), Ligand 1 (19 mg, 0.04 mmol, 4 mol %), pulverized KOH (168 mg, 3.0mmol), and 4-amino-benzoic acid (165 mg, 1.2 mmol). The flask wasevacuated and backfilled with argon (3×) and then capped with a rubberseptum. To the flask was added t-BuOH (2.0 mL), 4-n-butylchlorobenzene(168 mg, 1.0 mmol) and t-BuOH (0.5 mL). The septum was replaced with aTeflon screwcap, the flask was sealed, and the mixture was heated to100° C. with stirring until the starting aryl chloride was consumed byGC analysis (3 h). The reaction was cooled to room temperature, dilutedwith 5% aq. NaOH and extracted with Et₂O. The aqueous layer was cooledto 0° C. and acidified with HCl (12.0 M) until pH ˜4. The aqueous layerwas extracted with Et₂O, dried over anh. MgSO₄, filtered, andconcentrated under reduced pressure to give crude product (248 mg). Theproduct was purified by re-crystallizing in hot hexanes/chloroform togive faint brown platelets (209 mg, 78%).

3-(4-Methoxy-phenylamino)-benzamide

An oven-dried resealable Schlenk flask was evacuated and backfilled withargon. The flask was charged with Pd₂ dba₃ (9.2 mg, 0.01 mmol, 2 mol %Pd), Ligand 1 (19 mg, 0.04 mmol, 4 mol %), K₂CO₃ (304 mg, 2.2 mmol),3-chloro-benzamide (156 mg, 1.0 mmol), and 4-methoxy-aniline (148 mg,1.2 mmol). The flask was evacuated and backfilled with argon (3×) andthen capped with a rubber septum. To the flask was added t-BuOH (2.5mL). The septum was replaced with a Teflon screwcap, the flask wassealed, and the mixture was heated to 100° C. with stirring until thestarting aryl chloride was consumed by TLC analysis (20 h). The reactionwas cooled to room temperature, diluted with ethyl acetate, filteredthrough Celite, and concentrated under reduced pressure. The crudematerial was purified by column chromatography on silica gel (elutingwith EtOAc/hexanes, 8.5:1.5) to give the desired product which wasre-crystallized from ethyl acetate/hexanes (14/1) to give white flakycrystals (191 mg, 79%).

Example 60 Pd-Catalyzed Carbon-Nitrogen Bond Formation in tert-ButanolUsing (2′,4′,6′-triisopropylbiphenyl)dicyclohexylphosphine as Ligand

General Procedure

An oven-dried resealable Schlenk tube containing a stir bar was chargedwith Pd(OAc)₂ (2.3 mg, 0.01 mmol),2-di(cyclohexyl)phosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025mmol) and phenylboronic acid (3.1 mg, 0.025 mmol). The tube was cappedwith a rubber septum, evacuated and backfilled with argon. tButanol (0.5mL) was added through the septum via a syringe. The reaction mixture wasstirred at room temperature for 20 min. Aryl halide or sulfonate (0.5mmol), amine (0.75 mmol) and finely ground K₂CO₃ (173 mg, 1.2 mmol) wereadded into the schlenk tube under a flow of argon, followed by theaddition of tbutanol (0.5 mL) via a syringe. The septum was replacedwith a Teflon screw cap. The schlenk tube was sealed and put into apre-heated oil bath at 110° C. The reaction mixture was stirred for thetime specified and the resulting mixture was allowed to cool down toroom temperature, filtered through celite with ethyl acetate. Thefiltrate was concentrated under reduced pressure and the residue waspurified by chromatography on a silica gel column.

4-(3,5-Dimethylphenylamino)benzamide

Following the general procedure, 3,5-dimethylphenyl benzenesulfonate(131 mg, 0.5 mmol) was coupled with 4-aminobenzamide (102 mg, 0.75 mmol)with the reaction time of 6 h. Chromatography on silica gel column withethyl acetate gave 115 mg (96%) of the title compound as a white solid.

2-Phenylaminobenzamide

Following the general procedure, bromobenzene (55 μL, 0.5 mmol) wascoupled with 2-aminobenzamide (102 mg, 0.75 mmol) with the reaction timeof 15 h. Chromatography on silica gel column with 1:1 hexane:ethylacetate gave 74 mg (70%) of the title compound as a white solid.

2-(4-Cyanophenylamino)benzamide

Following the general procedure, 4-bromobenzonitrile (91 mg, 0.5 mmol)was coupled with 2-aminobenzamide (102 mg, 0.75 mmol) with the reactiontime of 17 h. Chromatography on silica gel column with 1:1 hexane:ethylacetate gave 103 mg (87%) of the title compound as a pale yellow solid.

N-(4-p-Tolylaminophenyl)acetamide

Following the general procedure, 4-chloroacetanilide (85 mg, 0.5 mmol)was coupled with p-toluidine (80 mg, 0.75 mmol) with the reactiontemperature of 90° C. and the reaction time of 14 h. Chromatography onsilica gel column with 2:1 hexane:ethyl acetate gave 118 mg (98%) of thetitle compound as a pink solid.

5-(3,5-Dimethylphenylamino)indole and1-(3,5-dimethylphenyl)-5-aminoindole

Following the general procedure, 3,5-dimethylphenyl benzenesulfonate(131 mg, 0.5 mmol) was coupled with 5-aminoindole (100 mg, 0.75 mmol)with the reaction time of 4 h. Chromatography on silica gel column with6:1 hexane:ethyl acetate gave 88 mg (74%) of5-(3,5-dimethylphenylamino)indole as a pale brown solid; and 16 mg (14%)of 1-(3,5-dimethylphenyl)-5-aminoindole as a white solid.

Ethyl 4-((3-aminophenyl)amino)benzoate

Following the general procedure, 3-bromoaniline (56 μL, 0.5 mmol) wascoupled with ethyl 4-aminobenzoate (125 mg, 0.75 mmol) with the reactiontemperature of 80° C. and the reaction time of 17 h. Chromatography onsilica gel column with 4:1 hexane:ethyl acetate gave 55 mg (43%) of thetitle compound as a pale brown solid.

N-(4-tButylphenyl)-2-pyrrolidinone

Following the general procedure, 4-tbutylphenyl benzenesulfonate (145mg, 0.5 mmol) was coupled with 2-pyrrolidinone (57 μL, 0.75 mmol) withthe reaction time of 21 h. Chromatography on silica gel column with 1:1hexane:ethyl acetate gave 103 mg (95%) of the title compound as a whitesolid.

N-(4-tButylphenyl)acetamide

Following the general procedure, 4-tbutylphenyl benzenesulfonate (145mg, 0.5 mmol) was coupled with acetamide (45 mg, 0.75 mmol) with thereaction time of 21 h. Chromatography on silica gel column with 1:1hexane:ethyl acetate gave 84 mg (88%) of the title compound as a whitesolid.

N-(3,5-dimethylphenyl)-N-methylformamide

Following the general procedure, 3,5-dimethylphenyl benzenesulfonate(131 mg, 0.5 mmol) was coupled with N-methylformamide (45 mg, 0.75 mmol)with the reaction time of 20 h. Chromatography on silica gel column with4:1 hexane:ethyl acetate gave 76 mg (93%) of the title compound as acolorless oil.

tButyl N-(3,4-methylenedioxyphenyl)carbamate

Following the general procedure, 3,4-methylenedioxyphenyl tosylate (146mg, 0.5 mmol) was coupled with tbutyl carbamate (90 mg, 0.75 mmol) withthe reaction time of 24 h and the exception that2-di-cyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (19.0 m g, 0.040m mol) was used. Chromatography on silica gel column with 10:1hexane:ethyl acetate gave 101 mg (85%) of the title compound as a whitesolid.

N-(1-Naphthyl)benzamide

Following the general procedure, 1-naphthyl tosylate (149 mg, 0.5 mmol)was coupled with benzamide (90 mg, 0.75 mmol) with the reaction time of20 h. Chromatography on silica gel column with 4:1 hexane:ethyl acetategave 117 mg (95%) of the title compound as a white solid.

Example 61

3-Morpholine-acetanilide

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd(OAc)₂ (2.3 mg, 0.01 mmol),2-di-cyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025mmol), 3-(N-acetyl)phenyl tosylate (153 mg, 0.5 mmol) and finely groundK₂CO₃ (173 mg, 1.2 mmol). The tube was capped with a rubber septum,evacuated and backfilled with argon. Morpholine (66 μL, 0.75 mmol) andtbutanol (1 mL) were added through the septum via syringe. The septumwas replaced with a Teflon screw cap. The schlenk tube was sealed andput into a pre-heated oil bath at 110° C. The reaction mixture wasstirred for 20 h, allowed to cool down to room temperature, filteredthrough celite with ethyl acetate. Chromatography on silica gel columnwith ethyl acetate gave 110 mg (100%) of the title compound as a whitesolid.

Example 62

N-(4-Hexylaminophenyl)acetamide

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd₂(dba)₃ (4.6 mg, 0.005 mmol),2-di-cyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025mmol), 4-bromoacetanilide (107 mg, 0.5 mmol) and sodium tbutoxide (120mg, 1.2 mmol). The tube was capped with a rubber septum, evacuated andbackfilled with argon. nHexylamine (100 μL, 0.75 mmol) and tbutanol (1mL) were added through the septum via syringe. The septum was replacedwith a Teflon screw cap. The schlenk tube was sealed and put into apre-heated oil bath at 110° C. The reaction mixture was stirred for 3 h,allowed to cool down to room temperature and quenched with water.Extraction with ethyl acetate three times followed by chromatography onsilica gel column with 1:1 hexane:ethyl acetate gave 95 mg (81%) of thetitle compound as a white solid.

Example 63

α-(4-tButylphenyl)cycloheptanone

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd(OAc)₂ (2.3 mg, 0.01 mmol),2-di-cyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025mmol), 4-tbutylphenyl benzenesulfonate (145 mg, 0.5 mmol) and Cs₂CO₃(408 mg, 1.2 mmol). The tube was capped with a rubber septum, evacuatedand backfilled with argon. Cycloheptanone (90 μL, 0.75 mmol), toluene (1mL) and 1-butanol (0.2 mL) were added through the septum via syringe.The septum was replaced with a Teflon screw cap. The schlenk tube wassealed and put into a pre-heated oil bath at 110° C. The reactionmixture was stirred for 21 h, allowed to cool down to room temperature,filtered through celite with ethyl acetate. Chromatography on silica gelcolumn with 30:1 hexane:ethyl acetate gave 104 mg (85%) of the titlecompound as a white solid.

Example 64

Diethyl α-(4-tbutylphenyl)malonate

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd(OAc)₂ (2.3 mg, 0.01 mmol),2-di-cyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025mmol), 4-tbutylphenyl benzenesulfonate (145 mg, 0.5 mmol) and Cs₂CO₃(408 mg, 1.2 mmol). The tube was capped with a rubber septum, evacuatedand backfilled with argon. Diethyl malonate (115 μL, 0.75 mmol) andtoluene (1 mL) were added through the septum via syringe. The septum wasreplaced with a Teflon screw cap. The schlenk tube was sealed and putinto a pre-heated oil bath at 110° C. The reaction mixture was stirredfor 18 h, allowed to cool down to room temperature, filtered throughcelite with ethyl acetate. Chromatography on silica gel column with 10:1hexane:ethyl acetate gave 131 mg (90%) of the title compound as acolorless oil.

Example 65

Ethyl α-phenyl-α-(4-tbutylphenyl)acetate

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd(OAc)₂ (2.3 mg, 0.01 mmol),2-di-cyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025mmol), 4-tbutylphenyl benzenesulfonate (145 mg, 0.5 mmol) and Cs₂CO₃(408 mg, 1.2 mmol). The tube was capped with a rubber septum, evacuatedand backfilled with argon. Ethyl α-phenylacetate (120 μL, 0.75 mmol),toluene (1 mL) and tbutanol (0.2 mL) were added through the septum viasyringe. The septum was replaced with a Teflon screw cap. The schlenktube was sealed and put into a pre-heated oil bath at 110° C. Thereaction mixture was stirred for 20 h, allowed to cool down to roomtemperature, filtered through celite with ethyl acetate. Chromatographyon silica gel column with 4:1 hexane:dichloromethane gave 130 mg (88%)of the title compound as a colorless oil.

Example 66 Suzuki Cross-Coupling Reactions of Aryl Tosylates withArylboronic Acids

General Procedure

Pd(OAc)₂ (1-2 mol %), phosphine ligand (2-5 mol %), aryl tosylate (1equiv), arylboronic acid (2 equiv) and a base (3 equiv) were added to aSchlenk tube equipped with a magnetic stir bar. The tube was evacuatedand backfilled with nitrogen or argon three times. Under a nitrogen orargon atmosphere, THF (1 mL) was added via a syringe. The tube wassealed with a Teflon screwcap and heated to the specified temperature inan oil bath for the time indicated. The reaction tube was allowed tocool to room temperature when the reaction was completed according toGC, TLC and/or crude ¹H NMR. Then, the reaction was quenched with 1 mLof 1M aqueous HCl and diluted with 5 mL of EtOAc. The organic layer wasseparated and the aqueous layer was washed with EtOAc (2×5 mL). Forpyridine and quinoline compounds, the reaction was quenched with 1 mL ofwater and the aqueous layer was washed repeatedly with EtOAc until allproduct was extracted. The combined organic layer was dried over MgSO₄.After filtering the MgSO₄, the filtrate was concentrated under reducedpressure. Column chromatography of the residue on silica gel withHexanes:EtOAc eluant afforded the product.

Numerous specific embodiments of the general method are presented inFIGS. 13-18.

Example 67

5-(4-nbutylphenylamino)indole and 1-(4-nbutylphenyl)-5-aminoindole

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd₂(dba)₃ (4.6 mg, 0.005 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025mmol), 5-aminoindole (100 mg, 0.75 mmol) and K₂CO₃ (173 mg, 1.25 mmol).The tube was capped with a rubber septum, evacuated and backfilled withargon. 4-nbutylchlorobenzene (85 mg, 0.5 mmol) and tbutanol (1 mL) wereadded through the septum via syringe. The septum was replaced with aTeflon screw cap. The schlenk tube was sealed and put into a pre-heatedoil bath at 110° C. The reaction mixture was stirred for 3 h, allowed tocool down to room temperature and filtered through celite with ethylacetate. The filtrate was concentrated under reduced pressure.Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave106 mg (80%) of 5-(4-nbutylphenylamino)indole as a pale brown solid.1-(4-nButylphenyl)-5-aminoindole was obtained in 10% GC yield.

Example 68

Ethyl 4-((3-aminophenyl)amino)benzoate

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd₂(dba)₃ (4.6 mg, 0.005 mmol),2-ditbutylphosphino-2′,4′,6′-triisopropylbiphenyl (17.0 mg, 0.04 mmol),ethyl 4-aminobenzoate (125 mg, 0.75 mmol) and K₂CO₃ (173 mg, 1.25 mmol).The tube was capped with a rubber septum, evacuated and backfilled withargon. 3-Bromoaniline (56 μL, 0.5 mmol) and tbutanol (1 mL) were addedthrough the septum via syringe. The septum was replaced with a Teflonscrew cap. The schlenk tube was sealed and put into a pre-heated oilbath at 80° C. The reaction mixture was stirred for 11 h, allowed tocool down to room temperature and filtered through celite with ethylacetate. The filtrate was concentrated under reduced pressure.Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave103 mg (80%) of the title compound as a pale yellow oil.

Example 69

2-(2-Methylphenylamino)benzamide and 2-amino-N-(2-methylphenyl)benzamide

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd₂(dba)₃ (4.6 mg, 0.005 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (19.0 mg, 0.04mmol), 2-aminobenzamide (170 mg, 1.25 mmol) and K₂CO₃ (173 mg, 1.25mmol). The tube was capped with a rubber septum, evacuated andbackfilled with argon. 2-Chlorotoluene (60 μL, 0.5 mmol) and tbutanol (1mL) were added through the septum via syringe. The septum was replacedwith a Teflon screw cap. The schlenk tube was sealed and put into apre-heated oil bath at 110° C. The reaction mixture was stirred for 17h, allowed to cool down to room temperature and filtered through celitewith ethyl acetate. The filtrate was concentrated under reducedpressure. Chromatography on silica gel column with 4:1 hexane:ethylacetate gave 98 mg (87%) of 2-(2-methylphenylamino)benzamide as a whitesolid and 11 mg (10%) of 2-amino-N-(2-methylphenyl)benzamide as a whitesolid.

Example 70

N-(2-p-Tolylaminophenyl)acetamide

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd₂(dba)₃ (4.6 mg, 0.005 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (19.0 mg, 0.04mmol), 2-bromoacetanilide (107 mg, 0.5 mmol), p-toluidine (80 mg, 0.75mmol) and K₃PO₄ (265 mg, 1.25 mmol). The tube was capped with a rubberseptum, evacuated and backfilled with argon. tbutanol (1 mL) was addedthrough the septum via syringe. The septum was replaced with a Teflonscrew cap. The schlenk tube was sealed and put into a pre-heated oilbath at 110° C. The reaction mixture was stirred for 18 h, allowed tocool down to room temperature and filtered through celite with ethylacetate. The filtrate was concentrated under reduced pressure.Chromatography on silica gel column with 1:1 hexane:ethyl acetate gave107 mg (89%) of the title compound as a brown solid.

Example 71

N-(3-Dibutylaminophenyl)acetamide

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd₂(dba)₃ (4.6 mg, 0.005 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.9 mg, 0.025mmol), 3-chloroacetanilide (85 mg, 0.5 mmol) and sodium tbutoxide (120mg, 1.25 mmol). The tube was capped with a rubber septum, evacuated andbackfilled with argon. Dinbutylamine (126 μL, 0.75 mmol) and tbutanol (1mL) were added through the septum via syringe. The septum was replacedwith a Teflon screw cap. The schlenk tube was sealed and put into apre-heated oil bath at 90° C. The reaction mixture was stirred for 18 h,allowed to cool down to room temperature and quenched with water.Extraction with ethyl acetate three times followed by chromatography onsilica gel column with 4:1 hexane:ethyl acetate gave 106 mg (81%) of thetitle compound as a pale yellow oil.

Example 72

2-Phenylaminobenzamide and 2-amino-N-phenylbenzamide using t-amylalcohol as solvent

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd₂(dba)₃ (4.6 mg, 0.005 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (19.0 mg, 0.04mmol), 2-aminobenzamide (102 mg, 0.75 mmol) and K₂CO₃ (173 mg, 1.25mmol). The tube was capped with a rubber septum, evacuated andbackfilled with argon. Bromobenzene (55 μL, 0.5 mmol) and tamyl alcohol(1 mL) were added through the septum via syringe. The septum wasreplaced with a Teflon screw cap. The schlenk tube was sealed and putinto a pre-heated oil bath at 110° C. The reaction mixture was stirredfor 15 h, allowed to cool down to room temperature. GC analysis showedfull conversion of bromobenzene. 2-Phenylaminobenzamide was obtained in65% GC yield and 2-amino-N-phenylbenzamide in 10% GC yield.

Example 73

N-(4-Hexylaminophenyl)acetamide using PtBu₃ as the ligand

An oven-dried resealable schlenk tube containing a stir bar was chargedwith Pd₂(dba)₃ (4.6 mg, 0.005 mmol) and 4-bromoacetanilide (107 mg, 0.5mmol). The tube was capped with a rubber septum, evacuated andbackfilled with argon. The tube was capped with a rubber septum,evacuated and backfilled with argon. The septum was replaced with aTeflon screw cap and the tube was brought into the glovebox. The tubewas charged with tritbutylphosphine (5.1 mg, 0.025 mmol) and sodiumtbutoxide (120 mg, 1.25 mmol) and sealed with Teflon screw cap. The tubewas brought out of the glovebox and the Teflon screw cap was replacedwith a rubber septum under a flow of argon. nHexylamine (100 μL, 0.75mmol) and tbutanol (1 mL) were added through the septum via syringe. Theseptum was replaced with a Teflon screw cap. The schlenk tube was sealedand put into a pre-heated oil bath at 110° C. The reaction mixture wasstirred for 3 h, allowed to cool down to room temperature and quenchedwith water. The aqueous layer was extracted with ethyl acetate threetimes. GC analysis of the organics showed the title compound wasobtained in 25% GC yield.

Example 74

Pd-Complex-Catalyzed Aminations in Water Using an Aryl Chloride andPotassium Hydroxide

A resealable Schlenk flask was charged with palladium complex (0.01mmol) and KOH (86 mg, 1.5 mmol). The flask was evacuated, backfilledwith argon and then, to it, were added 4-n-butylchlorobenzene (1 mmol),morpholine (1.2 mmol) and deionized, degassed water (0.5 mL). The flaskwas sealed with a teflon screwcap and the mixture was stirred at 110° C.for 18 h. After all starting material had been consumed, as judged byGC, the mixture was allowed to cool to room temperature and then wasdiluted with ether (40 mL). The resulting suspension was transferred toa separatory funnel and washed with water (10 mL). The organic layer wasseparated, dried with MgSO₄ and concentrated under vacuum. The crudematerial was purified by flash chromatography on silica gel.

Example 75

Pd-Complex-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Hydroxide

An oven-dried resealable Schlenk flask was charged with palladiumcomplex (8.3 mg, 0.01 mmol), and KOH (84 mg, 1.5 mmol). The flask wasevacuated, backfilled with argon and then, to it, were added4-n-butylchlorobenzene (170 μL, 1 mmol), aniline (109 μL, 1.2 mmol),dodecane as internal standard (15 mg) and water (0.5 mL). The flask wassealed with a teflon screwcap and the mixture was stirred at 110° C. for14 hours. After this time the reaction was cooled to room temperatureand the conversion and the yield were determined by gas chromatographyusing dodecane as an internal standard.

Example 76

Pd-Complex-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Hydroxide

An oven-dried resealable Schlenk flask was charged with palladiumcomplex (8.3 mg, 0.01 mmol), KOH (86 mg, 1.5 mmol) and indole (140 mg,1.2 mmol). The flask was evacuated, backfilled with argon and then, toit, were added 4-n-butylchlorobenzene (170 μL 1 mmol), and t-water (0.5mL). The flask was sealed with a teflon screwcap and the mixture wasstirred at 110° C. for 17 hours. After all starting material had beenconsumed, as judged by GC, the mixture was allowed to cool to roomtemperature and then was diluted with ether (40 m L). The resultingsuspension was transferred to a separatory funnel and washed with water(10 mL). The organic layer was separated, dried with MgSO₄ andconcentrated under vacuum. The crude material was purified by flashchromatography on silica gel.

Example 77

Pd-Complex-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Hydroxide

A resealable Schlenk flask was charged with palladium complex (8.3 mg,0.01 mmol), and KOH (84 mg, 1.5 mmol). The flask was evacuated,backfilled with argon and then, to it, were added3-trifluoromethylchlorobenzene (163 μL, 1 mmol), aniline (109 μL, 1.2mmol), dodecane as internal standard (15 mg) and water (0.5 mL). Theflask was sealed with a teflon screwcap and the mixture was stirred at110° C. for 3 hours. After this time the reaction w as cooled to roomtemperature and the conversion and the yield were determined by gaschromatography using dodecane as an internal standard.

Example 78

Pd-Complex-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Hydroxide

A resealable Schlenk flask was charged with palladium complex (8.3 mg,0.01 mmol), 4-chloronitrobenzene (158 mg, 1 mmol), and KOH (84 mg, 1.5mmol). The flask was evacuated, backfilled with argon and then, to it,were added aniline (109 μL, 1.2 mmol), dodecane as internal standard (15mg) and water (0.5 mL). The flask was sealed with a teflon screwcap andthe mixture was stirred at 50° C. for 3 hours. After this time thereaction was cooled to room temperature and the conversion and the yieldwere determined by gas chromatography using dodecane as an internalstandard.

Example 79

Pd-Complex-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Hydroxide

A resealable Schlenk flask was charged with palladium complex (8.3 mg,0.01 mmol), and KOH (84 mg, 1.5 mmol). The flask was evacuated,backfilled with argon and then, to it, were added 4-n-butylchlorobenzene(170 μL, 1 mmol), morpholine (104 μL, 1.2 mmol), dodecane as internalstandard (15 mg) and water (0.5 mL). The flask was sealed with a teflonscrewcap and the mixture was stirred at 110° C. for 2 hours. After thistime the reaction w as cooled to room temperature and the conversion andthe yield were determined by gas chromatography using dodecane as aninternal standard.

Example 80

Pd-Complex-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Hydroxide

A resealable Schlenk flask was charged with palladium complex (8.3 mg,0.01 mmol), cetyltrimethylammonium bromide (36.4 mg, 0.1 mmol) and KOH(84 mg, 1.5 mmol). The flask was evacuated, backfilled with argon andthen, to it, were added 4-n-butylchlorobenzene (170 μL, 1 mmol),morpholine (104 μL, 1.2 mmol), dodecane as internal standard (15 mg) andwater (0.5 mL). The flask was sealed with a teflon screwcap and themixture was stirred at 110° C. for 2 hours. After this time the reactionwas cooled to room temperature and the conversion and the yield weredetermined by gas chromatography using dodecane as an internal standard.

Example 81

Pd-Complex-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Carbonate

A resealable Schlenk flask was charged with palladium complex (0.01mmol) and K₂CO₃ (207 mg, 1.5 mmol). The flask was evacuated, backfilledwith argon and then, to it, were added 4-n-butylchlorobenzene (1 mmol),morpholine (1.2 mmol) and degassed. deionized water (0.5 mL). The flaskwas sealed with a teflon screwcap and the mixture was stirred at 110° C.for 18 hours. After all starting material had been consumed, as judgedby GC, the mixture was allowed to cool to room temperature and then wasdiluted with ether (40 mL). The resulting suspension was transferred toa separatory funnel and washed with water (10 mL). The organic layer wasseparated, dried with MgSO₄ and concentrated under vacuum. The crudematerial was purified by flash chromatography on silica gel.

Example 82

Pd-Complex-Catalyzed Amination in Water Using an Aryl Chloride andSodium Hydroxide

An oven-dried resealable Schlenk flask was charged with palladiumcomplex (8.3 mg, 0.01 mmol), and NaOH (60 mg, 1.5 mmol). The flask wasevacuated, backfilled with argon and then, to it, were added4-n-butylchlorobenzene (170 μL, 1 mmol), morpholine (104 μL, 1.2 mmol),dodecane as internal standard (15 mg) and water (0.5 mL). The flask wassealed with a teflon screwcap and the mixture was stirred at 110° C. for17 hours. After this time the reaction was cooled to room temperatureand the conversion and the yield were determined by gas chromatographyusing dodecane as an internal standard.

Example 83

Pd-Complex-Catalyzed Amination in Water Using an Aryl Chloride andSodium Hydroxide

An oven-dried resealable Schlenk flask was charged with palladiumcomplex (4.6 mg, 0.01 mmol), and NaOH (60 mg, 1.5 mmol). The flask wasevacuated, backfilled with argon and then, to it, were added4-n-butylchlorobenzene (170 μL, 1 mmol), morpholine (104 μL, 1.2 mmol),dodecane as internal standard (15 mg) and water (0.5 mL). The flask wassealed with a teflon screwcap and the mixture was stirred at 110° C. for17 hours. After this time the reaction was cooled to room temperatureand the conversion and the yield were determined by gas chromatographyusing dodecane as an internal standard.

Example 84

Pd₂(dba)₃-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Hydroxide

A resealable schlenk flask was evacuated and backfilled with argon. Theflask was charged with Pd₂(dba)₃ (4.6 mg, 0.005 mmol, 1 mol % Pd),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (9.5 mg, 0.02mmol, 2 mol %), and powdered KOH (78 mg, 1.4 mmol). The flask wasevacuated and backfilled with argon (3×) and capped with a rubberseptum. 2-Chloro-p-xylene (0.134 mL, 1.0 mmol), n-hexyl-amine (0.58 mL,1.2 mmol), and degassed water (0.5 mL) were added through the septum.The septum was replaced with a Teflon screwcap, the flask was sealed,and the mixture was heated to 110° C. with stirring. At 2 h, 54% of thearyl halide had been consumed with no further conversion upon re-heating(50% GC yield).

Example 85

Pd₂(dba)₃-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Hydroxide

A resealable schlenk flask was evacuated and backfilled with argon. Theflask was charged with Pd₂(dba)₃ (4.6 mg, 0.005 mmol, 1 mol % Pd),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (9.5 mg, 0.02mmol, 2 mol %), and powdered KOH (78 mg, 1.4 mmol). The flask wasevacuated and backfilled with argon (3×) and capped with a rubberseptum. 3-Chloro-pyridine (0.095 mL, 1.0 mmol), aniline (0.109 mL, 1.2mmol), and degassed water (0.5 mL) were added through the septum. Theseptum was replaced with a Teflon screwcap, the flask was sealed, andthe mixture was heated to 110° C. with stirring until the starting arylhalide had been consumed by GC analysis (6 h). After completeconsumption of the aryl halide, the reaction was cooled to roomtemperature, diluted with ethyl acetate, filtered through celite andconcentrated under reduced pressure. The crude material was purified bycolumn chromatography on silica gel (eluting with 70% ethyl acetate inhexanes) to give the desired product as a white solid (162 mg, 95%).

Example 86

Pd(II) Acetate-Catalyzed Amination in Water Using an Aryl Chloride andPotassium Hydroxide

A resealable Schlenk flask was charged with palladium acetate (2.2 mg,0.01 mmol), ligand (9.5 mg, 0.02 mmol) and KOH (86 mg, 1.5 mmol). Theflask was evacuated, backfilled with argon. Then, 4-n-butylchlorobenzene(170 mL, 1 mmol), morpholine (104 mL, 1.2 mmol), dodecane (as internalstandard; 15 mg) and water (0.5 mL) were added. The flask was sealedwith a teflon screwcap and the mixture was stirred at 110° C. for 16hours. The reaction was allowed to cool to room temperature and theconversion and the yield were determined by gas chromatography usingdodecane as an internal standard.

Example 87

Pd(II) Acetate-Catalyzed Amination in Water Using an Aryl Chloride andSodium Hydroxide

A resealable Schlenk flask was charged with palladium acetate (2.2 mg,0.01 mmol), ligand (9.5 mg, 0.02 mmol) and NaOH (60 mg, 1.5 mmol). Theflask was evacuated, backfilled with argon. Then, 4-n-butylchlorobenzene(170 mL, 1 mmol), morpholine (104 mL, 1.2 mmol), dodecane (internalstandard; 15 mg) and water (0.5 mL) were added. The flask was sealedwith a teflon screwcap and the mixture was stirred at 110° C. for 16hours. The reaction was allowed to cool to room temperature and theconversion and the yield were determined by gas chromatography usingdodecane as an internal standard.

Example 88

Pd(II) Acetate-Catalyzed Aminations in Water Using an Aryl Bromide andPotassium Hydroxide Using Various Ligands

4-Toluidine (129 mg, 1.2 mmol), Pd(OAc)₂, (2.3 mg, 0.01 mmol), ligand(0.025 mmol), and KOH (78 mg 1.4 mmol) were charged to a Schlenk tube.The tube was pumped and refilled with argon twice; then, 4-t-butylbromobenzene (213 mg, 0.177 mL, 1 mmol) and water (0.5 mL) were added.The resulting mixture was refluxed at 110° C. for 12 h. The productswere analyzed by GC analysis (with dodecane as internal standard).

The reaction was performed using BINAP as ligand (15 mg). GC conversion:67%, GC yield 65%.

The reaction was performed using tri-tert-butylphosphine as ligand,generated in situ using tri-t-butylphosphonium tetrafluoroborate (8 mg),which reacts with the KOH: GC Conversion 99%, GC yield 97%.

The reaction was performed using ligand 1 (12 mg), GC Conversion 99%, GCyield 98%.

The reaction was performed using1,3-Bis(2,6-di-iso-propylphenyl)-4,5-dihydro-imidazoliumtetrafluoroborate, GC Conversion 10%, GC yield 5%.

Example 89

Pd(II) Acetate-Catalyzed Aminations in Water Using an Aryl Bromide andTributylamine Using Various Ligands

4-Toluidine (129 mg, 1.2 mmol), Pd(OAc)₂, (2.3 mg, 0.01 mmol), and aligand (0.025 mmol), were charged to a Schlenk tube. The tube was pumpedand refilled with argon twice; then, 4-t-butyl bromobenzene (213 mg,0.177 mL, 1 mmol), tributylamine (0.332 mL mg 1.4 mmol), and water (0.5mL) were added. The resulting mixture was refluxed at 110° C. for 3 h.The products were analyzed by GC analysis (with dodecane as internalstandard).

The reaction was performed using BINAP as ligand (15 mg). GC conversion:1%, GC yield less than 1%.

The reaction was performed using tri-t-butylphosphoniumtetrafluoroborate as ligand (8 mg). GC Conversion 2%, GC yield 1%.

The reaction was performed using ligand 1 (12 mg). GC Conversion 3%, GCyield 2%.

The reaction was performed using1,3-bis(2,6-di-iso-propylphenyl)-4,5-dihydro-imidazoliumtetrafluoroborate. GC Conversion less than 1%, GC yield less than 1%.

Example 90

Pd(II) Acetate-Catalyzed Aminations in Water Using an Aryl Bromide andPotassium Hydroxide Using Various Ligands without Using PhenylboronicAcid

4-Toluidine (129 mg, 1.2 mmol), Pd(OAc)₂, (2.3 mg, 0.01 mmol), a ligand(0.025 mmol), and KOH (78 mg 1.4 mmol) were charged to a Schlenk tube.The tube was pumped and refilled with argon twice. Then, 4-t-butylbromobenzene (213 mg, 0.177 mL, 1 mmol) and water (0.5 mL) were added.The resulting mixture was refluxed at 110° C. for 12 h. The productswere analyzed by GC analysis (using dodecane as internal standard).

The reaction was performed using tri-t-butylphosphoniumtetrafluoroborate as ligand (8 mg). GC Conversion 99%, GC yield 85%.

The reaction was performed using ligand 1 (12 mg). GC Conversion 99%, GCyield 98%.

Example 91

Pd(II) Acetate-Catalyzed Aminations in Water Using an Aryl Bromide andSodium Hydroxide Using Various Ligands

4-Toluidine (129 mg, 1.2 mmol), Pd(OAc)₂, (2.3 mg, 0.01 mmol), ligand(0.025 mmol), and NaOH (78 mg, 1.4 mmol) were charged to a Schlenk tube.The tube was pumped and refilled with argon twice; then, 4-t-butylbromobenzene (213 mg, 0.177 mL, 1 mmol) and water (0.5 mL) were added.The resulting mixture was refluxed at 110° C. for 3 h. The products wereanalyzed by GC analysis (with dodecane as internal standard).

The reaction was performed using BINAP as ligand (15 mg). GC conversion:4%, GC yield 2%.

The reaction was performed using tri-tert-butylphosphoniumtetrafluoroborate as ligand (8 mg), GC Conversion 99%, GC yield 97%.

The reaction was performed using ligand 1 (12 mg), GC Conversion 99%, GCyield 98%.

The reaction was performed using1,3-Bis(2,6-di-iso-propylphenyl)-4,5-dihydro-imidazoliumtetrafluoroborate, GC Conversion 1%, GC yield 1%.

Example 92

Pd-Complex-Catalyzed Amination in tert-Butanol Using an Aryl Chlorideand Potassium Carbonate

An oven-dried resealable Schlenk flask was charged with palladiumcomplex (0.01 mmol) and K₂CO₃ (207 mg, 1.5 mmol). The flask wasevacuated, backfilled with argon and then, to it, were added4-n-butylchlorobenzene (1 mmol), morpholine (1.2 mmol) and t-buthanol (1mL). The flask was sealed with a teflon screwcap and the mixture wasstirred at 110° C. for 18 hours. After all starting material had beenconsumed, as judged by GC, the mixture was allowed to cool to roomtemperature and then was diluted with ether (40 mL). The resultingsuspension was transferred to a separatory funnel and washed with water(10 mL). The organic layer was separated, dried with MgSO₄ andconcentrated under vacuum. The crude material was purified by flashchromatography on silica gel.

Example 93

Pd-Complex-Catalyzed Amination in tert-Butanol Using an Aryl Chlorideand Potassium Hydroxide

An oven-dried resealable Schlenk flask was charged with palladiumcomplex (0.01 mmol) and KOH (86 mg, 1.5 mmol). The flask was evacuated,backfilled with argon and then, to it, were added 4-n-butylchlorobenzene(1 mmol), morpholine (1.2 mmol) and t-butanol (1 mL). The flask wassealed with a teflon screwcap and the mixture was stirred at 110° C. for18 h. After all starting material had been consumed, as judged by GC,the mixture was allowed to cool to room temperature and then was dilutedwith ether (40 mL). The resulting suspension was transferred to aseparatory funnel and washed with water (10 mL). The organic layer wasseparated, dried with MgSO₄ and concentrated under vacuum. The crudematerial was purified by flash chromatography on silica gel.

Incorporation by Reference

All patents and publications cited herein are hereby incorporated byreference.

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

1. A ligand represented by structure I:

wherein R is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, and —(CH₂)_(m)—R₈₀; the A and A′ rings of the biphenylcore independently may be unsubstituted or substituted with R₁ and R₂,respectively, any number of times up to the limitations imposed bystability and the rules of valence; R₁ and R₂, when present, areselected independently for each occurrence from the group consisting ofethyl, propyl, butyl, pentyl, hexyl, cycloalkyl, heterocycloalkyl,heteroaryl, aralkyl, heteroaralkyl, —Si(R)₃, and —(CH₂)_(m)—R₈₀; R₈₀represents an unsubstituted or substituted aryl, a cycloalkyl, acycloalkenyl, a heterocycle, or a polycycle; m is independently for eachoccurrence an integer in the range 0 to 8 inclusive; and the ligand,when chiral, is a mixture of enantiomers or a single enantiomer.
 2. Theligand of claim 1, wherein R represents independently for eachoccurrence ethyl, propyl, butyl, pentyl, hexyl, cycloalkyl or aryl; atleast two instances of R₂ are present; and R₂ is selected independentlyfor each occurrence from the group consisting of ethyl, propyl, butyl,pentyl, hexyl, and cycloalkyl.
 3. A ligand represented by structure II:

wherein R is selected independently for each occurrence from the groupconsisting of cycloalkyl, and —(CH₂)_(m)—R₈₀; R′ is selectedindependently for each occurrence from the group consisting of alkyl,cycloalkyl, and —(CH₂)_(m)—R₈₀; the A and A′ rings of the biphenyl coreindependently may be unsubstituted or substituted with R₁ and R₂,respectively, any number of times up to the limitations imposed bystability and the rules of valence; R₁ and R₂, when present, areselected independently for each occurrence from the group consisting ofalkyl, cycloalkyl, halogen, —Si(R)₃, and —(CH₂)_(m)—R₈₀; R₈₀ representsindependently for each occurrence cycloalkyl or aryl; m is independentlyfor each occurrence an integer in the range 0 to 8 inclusive; and theligand, when chiral, is a mixture of enantiomers or a single enantiomer.4. The ligand of claim 3, wherein R₁ is absent; and R₂ is absent.
 5. Theligand of claim 3, wherein R represents independently for eachoccurrence cycloalkyl.
 6. The ligand of claim 3, wherein R representsindependently for each occurrence, cyclohexyl, or cyclopropyl.
 7. Theligand of claim 3, wherein R represents independently for eachoccurrence cyclohexyl.
 8. The ligand of claim 3, wherein R′ representsindependently for each occurrence alkyl.
 9. The ligand of claim 3,wherein R′ represents independently for each occurrence isopropyl. 10.The ligand of claim 3, wherein R₁ is absent; R₂ is absent; and Rrepresents independently for each occurrence cycloalkyl.
 11. The ligandof claim 3, wherein R₁ is absent; R₂ is absent; and R representsindependently for each occurrence cyclohexyl, or cyclopropyl.
 12. Theligand of claim 3, wherein R₁ is absent; R₂ is absent; and R representsindependently for each occurrence cyclohexyl.
 13. The ligand of claim 3,wherein R₁ is absent; R₂ is absent; R represents independently for eachoccurrence cycloalkyl; and R′ represents independently for eachoccurrence alkyl.
 14. The ligand of claim 3, wherein R₁ is absent; R₂ isabsent; R represents independently for each occurrence cyclohexyl, orcyclopropyl; and R′ represents independently for each occurrence alkyl.15. The ligand of claim 3, wherein R₁ is absent; R₂ is absent; Rrepresents independently for each occurrence cyclohexyl; and R′represents independently for each occurrence alkyl.
 16. The ligand ofclaim 3, wherein R₁ is absent; R₂ is absent; R represents independentlyfor each occurrence or cycloalkyl; and R′ represents independently foreach occurrence isopropyl.
 17. The ligand of claim 3, wherein R₁ isabsent; R₂ is absent; R represents independently for each occurrencecyclohexyl, or cyclopropyl; and R′ represents independently for eachoccurrence isopropyl.
 18. The ligand of claim 3, wherein R₁ is absent;R₂ is absent; R represents independently for each occurrence cyclohexyl;and R′ represents independently for each occurrence isopropyl.
 19. Aligand represented by structure III:

wherein R′ is selected independently for each occurrence from the groupconsisting of alkyl, cycloalkyl, and —(CH₂)_(m)—R₈₀; the A and A′ ringsof the biphenyl core independently may be unsubstituted or substitutedwith R₁ and R₂, respectively, any number of times up to the limitationsimposed by stability and the rules of valence; R₁ and R₂, when present,are selected independently for each occurrence from the group consistingof alkyl, cycloalkyl, halogen, —Si(R)₃, and —(CH₂)_(m)—R₈₀; R₈₀represents independently for each occurrence cycloalkyl or aryl; m isindependently for each occurrence an integer in the range 0 to 8inclusive; and the ligand, when chiral, is a mixture of enantiomers or asingle enantiomer.
 20. The ligand of claim 19, wherein R₁ is absent; andR₂ is absent.
 21. The ligand of claim 19, wherein R′ representsindependently for each occurrence alkyl.
 22. The ligand of claim 19,wherein R′ represents independently for each occurrence isopropyl. 23.The ligand of claim 19, wherein R₁ is absent; R₂ is absent; and R′represents independently for each occurrence alkyl.
 24. The ligand ofclaim 19, wherein R₁ is absent; R₂ is absent; and R′ representsindependently for each occurrence isopropyl.